- freely available
Molecules 2014, 19(5), 5717-5747; doi:10.3390/molecules19055717
Published: 5 May 2014
Abstract: Essential oils have attracted considerable worldwide attention over the last few decades. These natural products have wide-ranging pharmacological activities and biotechnological applications. Faced with the need to find new anti-ulcer agents and the great effort on the development of drugs for the treatment of ulcers, in this review, the anti-ulcer activities of 21 bioactive compounds found in essential oils are discussed.
Peptic ulcer disease is a chronic pathology that affects millions of people worldwide. It is believed that 10% of the population will develop this condition at some point in their lives . Peptic ulcers are usually classified by their anatomic location, such as gastric or duodenal ulcers, and increased gastric acid is the main cause. There is a strong association between H. pylori infection and duodenal ulcers. H. pylori causes an inflammatory response in the gastric mucosa, with increased production of cytokines  and influx of neutrophils and macrophages into the gastric mucosa with release of leukotrienes (LT) and reactive oxygen species, which makes the defense of the mucosa and stimulates of ulcer formation process .
The disease process of peptic ulcers is multifactorial based on etiology and risk factors. Ulcers result from an imbalance between aggressive factors, including hydrochloric acid; Helicobacter pylori infection; excessive intake of anti-inflammatory drugs, alcohol, pepsin, and reactive oxygen species; and cytoprotective factors, which include mucus, bicarbonate, prostaglandins, blood flow, and cellular repair, as well as enzymatic and non-enzymatic antioxidants [4,5,6].
Currently, the goals of treatment of peptic ulcer are based on pain relief, heal the ulcer and prevent recurrence of the ulcer . Thus, gastric ulcer treatment options include antacids (aluminum hydroxide and magnesium trisilicate), cytoprotective agents (sucralfate and the prostaglandin analogue misoprostol), muscarinic antagonists (pirenzepine), antimicrobial agents for eradication of H. pylori (amoxicillin and clarithromycin), H2 receptor antagonists (cimetidine andranitidine), and proton pump inhibitors (omeprazole and lansoprazole) [8,9]. Many adverse effects are associated with the prolonged use of H2 receptor blockers and proton pump inhibitors: hypersensitivity, arrhythmia, impotence, gynecomastia, and hypomagnesemia . Moreover, some of these treatments are expensive , and may increase susceptibility to fractures, pneumonia, and gastric cancer . Thus, research to develop new therapeutic agents for gastric ulcer treatment is necessary. In this context, medicinal plants are known to be important resources of bioactive molecules with anti-ulcerogenic potential [12,13]. Several plants have been used in traditional medicine for their anti-ulcerogenic properties. Among medicinal plants, the aromatic species have been used since antiquity because of therapeutic properties that are traditionally attributed to the presence of essential oils [14,15].
Essential oils are complex mixtures of volatile compounds, and are characterized by a strong odor. They comprise mainly of two biosynthetically distinct groups of low-weight molecules: terpenes and phenylpropanoids. Phenylpropane derivatives and aromatic compounds are found less frequently than terpenes .
Terpenes found in essential oils are classified as monoterpenes and sesquiterpenes, and these are considered primary classes of secondary metabolites for anti-ulcer activity research . Recently, Rozza and collaborators  examined the activity of some essential oils traditionally used in the treatment of gastric ulcers, and considered their families and the part of the plant from which the oils were isolated.
This article reviews studies in the English-language literature on essential oil constituents with anti-ulcer activity. Chemical structures and names of bioactive compounds are provided. The compounds presented in this review were selected with reference to pharmacological action shown in specific experimental models for evaluation of anti-ulcer activity, and/or by complementary studies aimed to elucidate mechanisms of action. The selection of essential oil constituents in the database was performed using various terms, including essential oils, monoterpenes, sesquiterpenes, and phenylpropanoids, as well as names of representative compounds of these groups, and refined with terms relating to anti-ulcer activity, anti-ulcerogenic activity, and ulcers. The search was performed using the Chemical Abstracts Service and Pubmed in November 2013.
2. Results and Discussion
Menthol [5-methyl-2-(1-methylethyl)cyclohexanol, 2-isopropyl-5-methylcyclohexanol, or p-methan-3-ol] is a cyclic monoterpene alcohol that is found as a major constituent in the essential oils of Mentha canadensis L (American wild mint) and Mentha x piperita L (peppermint) . Menthol’s safety profile has been demonstrated by in vitro and in vivo studies and investigations show a low potential for toxicity in humans .
Rozza and collaborators  recently showed that oral administration of menthol (50 mg/kg) produced a substantial protective action on the gastric mucosa (88% and 72% against ethanol and indomethacin, respectively). Moreover, the protective mechanism appears to involve increased production of mucus and PGE2, with the involvement of SH compounds and stimulation of K+ATP channels, but not the activation of calcium ion channels or the production of nitric oxide. In rats with 4-h pylorus ligation, oral pretreatment with menthol significantly reduced total acid output without modifying its volume. However, intra-duodenal menthol administration diminished the volume of gastric juice, but did not decrease the H+ concentration. This study also showed that menthol possesses antiperistaltic activity and no signs of toxicity when orally administered (500 mg/kg) over a period of 14 days.
Considerable attention has been focused on development of ibuprofen prodrugs by selecting various promoieties with the aim of reducing GI toxicity [21,22]. In this direction,  have demonstrated improving therapeutic efficacy of racemic ibuprofen (150 mg/kg, p.o.) by retarding gastrointestinal side effects by synthesis and evaluation of ester derivatives of ibuprofen as mutual prodrugs with promoieties like menthol (IME), thymol (ITE) and eugenol (IEE). The results revealed increased anti-inflammatory activity that might be attributed to synergistic effect as ibuprofen conjugates to natural agents. Furthermore the ulcer index shows much reduction in gastric ulceration compared to ibuprofen (2.41 ± 0.27; 0.91 ± 0.15 (IME); 0.83 ± 0.17 (ITE); 1.08 ± 0.15 (IEE)). Finally the studies showed that prodrug approach can be successfully applied in attaining the goal of minimized gastrointestinal toxicity with retention of desired anti-inflammatory activity.
Isopulegol (p-menth-8-en-3-ol) is a monoterpene found in essential oils of various species, such as Corymbia citriodora Hill & Johnson [24,25] and Zanthoxylum schinifolium Siebold. & Zucc. . This monoterpene belongs to the p-menthane family and is used as an intermediate in the preparation of (‒)-menthol , and in the manufacture of perfumes, shampoos, and soaps . LD50 values in rats treated orally have been reported for isopulegol is 1.03 g/kg bw;  and shows no toxicity  Silva and collaborators , demonstrated that isopulegol (100 and 200 mg/kg) significantly reduced gastric lesions induced by absolute ethanol in mice. Acute administration of ethanol to rodents produces gastric mucosal damage that involves intracellular oxidative stress, inhibition of prostaglandins, intracellular thiol groups, and microcirculation disturbances [32,33]. Therefore, the pathogenesis of ethanol-induced lesions is multifactorial, and this model is widely used to study the cytoprotective potential of drugs .
Isopulegol prevented the reduction of non-protein sulfhydryl groups in the gastric mucosa and inhibited ethanol-induced histopathological changes. Hemorrhage, edema, infiltration of inflammatory cells, and reduction of endogenous sulfhydryl levels are characteristicsof damage due to the acute administration of ethanol [34,35]. Taken together, these data indicate significant protective effects of isopulegol, and suggest antioxidant activity.
The roles of prostaglandins, nitric oxide, and ATP-sensitive K+ channels (KATP channels) in the cytoprotective effects of isopulegol were evaluated in the ethanol-induced lesion model after pretreatment of mice with indomethacin, a non-selective cyclooxygenase inhibitor. Indomethacin, an NSAID, caused gastric lesions by the inhibition of prostaglandin biosynthesis, leading to a decrease in gastroprotection, increase in acid secretion, and exacerbation of ulcers . Prostaglandins are responsible for maintaining the integrity of the gastric mucosa by stimulating mucus and bicarbonate secretion , and nitric oxide appears to be a major regulator of blood flow and gastric microcirculation . Endogenous prostaglandins act as activators of KATP channels, and this mechanism, at least in part, mediates gastroprotection in rats .
These results show that prostaglandins and potassium channels, but not nitric oxide, participate in the gastroprotective effect of isopulegol, and suggest that isopulegol acts as a cytoprotective agent.
d-Limonene [the R-(+) isomer] is a monoterpene found in the essential oils of many plants, such as Artemisia dracunculus L , Ziziphora taurica subsp. cleonioides P.H. Davis , and species of Protium such as P. icicariba (DC.) Marchand  and P. heptaphyllum (Aubl.) Marchand . Because of its pleasant citrus fragrance, d-limonene is widely used as a flavoring agent in foods and beverages, and is considered to be a low toxicity ingredient .
Studies using pure limonene or essential oils containing R-(+)-limonene have demonstrated gastroprotective activity in animal models [45,46,47]. Rozza and collaborators  showed that the essential oil of Citrus lemon L (250 mg/kg) and limonene (177 mg/kg) exerted marked protection of the gastric mucosa in the ethanol-induced lesion model, and increased expression of the HSP-70 protein, which is associated with cellular adaptive protection processes in response to ethanol ingestion , suggesting cytoprotective action. The authors further demonstrated that the essential oil of C. lemon and limonene were able to increase levels of mucus and VIP, which were at least partly responsible for the gastroprotective effect of limonene. Gastric wall mucus protects the stomach from injury, and ethanol VIP acts by modulating the effects of histamine, and acting as an anti-inflammatory and antioxidant agent, preventing the formation of gastric ulcers .
It is well documented in the literature that the development of ethanol-induced gastric damage is accompanied by decreases in mucosal sulfhydryl compounds . These compounds are neutralized when they bind to the free radicals that are produced following tissue injury by noxious agents. Regulation of levels of GSH, NO participation, and NP-SH compounds should not be considered gastroprotective mechanisms of the essential oil of C. lemon or of limonene. The maintenance of PGE2 levels is part of the gastroprotective mechanism of essential oil of C. lemon, but not of limonene, suggesting that other components contribute actively to the gastroprotective effects of the essential oil.
Helicobacter pylori is an opportunistic pathogen associated with the pathogenesis of chronic gastritis, peptic ulcer, and gastric cancer, and is a global health concern . Antibiotic drug resistance is a major problem in treatment of H. pylori infections , and thus the search for safe and effective non-antibiotic agents is essential. Limonene showed activity against H. pylori with MIC of 75 mg/mL. A result less than or equal to 100 mg/mL MIC is a satisfactory result for products of a natural origin . Thus, these results show potential for the development of limonene as a new treatment for management of H. pylori infection.
Citrus aurantium, popularly known as bitter orange, is traditionally used in gastrointestinal disorders and rheumatism . Limonene is the main constituent of the essential oil from the peel of the bitter orange fruit . The integrity of the gastric mucosa depends on the balance between aggressive factors and protective mechanisms. One of the current approaches to the treatment of peptic ulcer disease is the inhibition of acid secretion and the promotion of cytoprotection or gastroprotection (participation of endogenous factors in gastric mucosal protection through mechanisms not associated with inhibition of acid secretion) [38,55,56].
Moraes and collaborators  characterized the effects of the essential oil of C. aurantium L and limonene in animal models of gastric ulcers. In the ethanol-induced gastric ulcer and NSAID models, both the essential oil of C. aurantium and limonene (250 and 245 mg/kg, respectively) exerted gastroprotective effects. This result suggests gastric mucosal protective activity of the essential oil of C. aurantium and limonene [57,58]. In the ligated pylorus model, it was observed that neither C. aurantium oil nor limonene were able to alter parameters of gastric secretion, suggesting that the gastroprotective effect of these products does not occur as a result of antisecretory action. These are interesting data, because the long-term use of proton pump inhibitors or H2 receptor blockers can cause serious adverse effects .
Mucus plays an important role in gastroprotection, maintaining the integrity of mucous membranes and neutralizing acid . The essential oil of C. aurantium and limonene were tested in a model of ethanol-induced gastric injury, and results showed an increase in the amount of mucus adherence in animals treated with the essential oil and limonene, which underlies their gastroprotective action. Oxidative stress induces gastric mucosal ischemia, leading to increased production of ROS and lipid peroxidation. In this context, increased levels of SOD play an important role in protection from oxidative stress . Moreover, neither C. aurantium oil nor limonene changed levels of GSH or SOD in the ethanol injury model, suggesting that the protective effect exhibited by these products is not related to antioxidant activity, but is instead due to increased production of mucus. This conclusion was confirmed in the indomethacin ulcer model. In this experiment, both C. aurantium essential oil and limonene were able to maintain levels of PGE2 similar to those found in the mice treated with vehicle, without modifying basal levels of PGE2. This result implicates the mucus-protective actions of the essential oil of C. aurantium and limonene in their gastroprotective effects.
Cineole (also known as 1,8-cineole, epoxy-p-menthane, or eucalyptol) is the primary monoterpene (80%) found in eucalyptus essential oil, and is also present in essential oils of other genera, including Artemisia, Salvia, and Mentha . Cineole is commonly used as a flavoring agent in the food industry and can be found in numerous cleaning products and cosmetics, including toothpastes, soaps, and creams, where it can be absorbed through the skin . This monoterpene shows very low toxicity, the oral LD50 was 2.48 g/kg body weight in the rat showing very low toxicity. Cineole is used in traditional medicine for the treatment of respiratory tract infections . The gastroprotective activity of cineole was investigated using the absolute ethanol gastric lesion model in rats . Male Wistar rats that were pretreated orally with cineole (50 to 200 mg/kg) showed a significant reduction in lesions, and 200 mg/kg was found to be the most potent dose, with effects comparable to those produced by nordihydroguaiaretic acid (NDGA; 75 mg/kg), a lipoxygenase inhibitor .
Lipoxygenase seems to play an important role as a mediator of inflammatory responses in gastric ulcers . Leukotriene LTC is an arachidonic acid metabolite produced by lipoxygenase that produces inflammatory vasoconstriction in the gastric mucosa in vivo. Ethanol-induced gastric lesions are accompanied by increased production of LTB4 and LTC4, and various non-specific inhibitors of leukotriene synthesis have been shown to prevent this type of damage in the gastric mucosa . Cineole prevented gastric injuries induced by ethanol (50–200 mg/kg), suggesting inhibition of lipoxygenase. This result confirmed the results of the study by Juergnes and collaborators  that demonstrated inhibition of arachidonic acid metabolism and generation of leukotrienes after cineole treatment. Santos and Rao  showed that cineole (100 and 200 mg/kg) attenuated the ethanol-induced decrease in gastric non-protein sulfhydryl levels, suggesting an antioxidant effect. The antioxidant activity of cineole was confirmed by Santos and collaborators  who showed that cineole (400 mg/kg) restored glutathione (GSH) levels and reduced myeloperoxidase (a biochemical marker of neutrophil infiltration in inflamed tissues) activity in a model of trinitrobenzene sulfonic acid (TNBS)-induced colitis, and exerted anti secretory activity in the ligated pylorus model in rats.
The ligated pylorus model is widely used to study drug effects on gastric acid secretion. Pylorus ligation increases the secretion of hydrochloric acid, leading to self-digestion and destruction of gastric mucosa barrier mucus. These events are associated with the development of lesions and ulcers in the upper gastrointestinal tract, leading to perforation and bleeding . Agents that reduce gastric acid secretion and increase mucus secretion are effective in protecting against ulcers. Cineole increased the volume and acidity of gastric secretion. Together, these data show the potential of cineole as an agent for the treatment of gastric ulcers. However, the effect of cineole in the ethanol injury model seems to be independent of its effect on gastric secretion and gastric mucus, because gastroprotection was observed at almost all doses.
Thymoquinone (TQ), the primary constituent of volatile oil from Nigela sativa seeds, has been reported to inhibit the generation of eicosanoids in leukocytes by inhibiting lipid peroxidation in phospholipid liposomes in the brain , and has also shown antioxidant activity . Evidence indicates that TQ has a protective role against gastric ulcers. El-Abhar and collaborators  demonstrated that TQ increased levels of SOD and glutathione, and reduced generation of leukotrienes, which were related to its gastroprotective effects in a rat model of reperfusion ischemia. Ischemia and reperfusion are known to induce gastric lesions predominantly because of excessive formation of reactive oxygen metabolites, adhesion of neutrophils to endothelial cells, and microvascular dysfunction . From this study, it may be concluded that the gastroprotective action of TQ can be attributed, at least in part, to its reactive oxygen species-scavenging ability.
Following the study of El-Abhar and collaborators , Arslan and collaborators  investigated the antioxidant capacity of TQ, and showed that decreased GSH and increased MDA levels in the ethanol-induced ulcer model were reversed by TQ (20 mg/kg), but that the compound produced only a minor non-significant decrease in SOD activity. Kanter and collaborators  also investigated the antioxidant effects of TQ in a rat mode of acute ethanol-induced gastric mucosal lesions, and found that TQ (10 mg/kg) mitigated most of the biochemical adverse effects induced by alcohol in the gastric mucosa, such as effects on MDA, SOD, and GSH. However, these effects were observed to a lesser extent than with the essential oil of N. sativa L.
The gastroprotective effects of TQ might be mediated by an antihistamine effect. Ohta and collaborators  showed that acutely released endogenous serotonin contributed to formation of gastric mucosal lesions in rats treated once with mast cell degranulator C48/80, while endogenous histamine release contributed to lesion progression . In fact, antihistamine action has been shown to be an important preventive mechanism against gastric injury produced by ethanol .
Kanter and collaborators  showed that gastric tissue histamine levels and MPO activity were increased in ethanol-treated rats, and treatment with N. sativa (500 mg/kg) or TQ (10 mg/kg) reversed this effect. These results are in agreement with those obtained by Chakravarty , who showed that N. sativa and nigellon (polymer of carbonyl TQ isolated from N. sativa) inhibited histamine release from rat peritoneal mast cells in vitro. This effect might be related to a reduction in c-AMP level, which may be owing to inhibition of adenylate cyclase or stimulation of phosphodiesterase activity. Taken together, these results suggest that N. sativa and TQ promote gastroprotection through antioxidant and antihistaminic effects.
Magdy and collaborators  recently investigated the mechanisms of TQ gastroprotection by studying its effect on gastric mucosal proton pump (H+/K+-ATPase) activity, gastric juice components, mucin level, nitric oxide metabolites, and neutrophil infiltration using the hypoxia/reoxygenation model. TQ-treated (20 mg/kg) rats showed marked protection against ischemia/reperfusion insult (I/R). TQ decreased several noxious factors such as acid output, lipid peroxide level, and neutrophil infiltration. TQ-mediated decreases in acid levels were attributed to its ability to normalize proton pump activity in parietal cells and/or antihistaminic activity. TQ also reduced the peptic activity of gastric juice, which may have involved inhibition of histamine release and/or decreased gastric acidity, which attenuated the activation of pepsinogens in the gastric juice. TQ also reduced neutrophil invasion, as evidenced by the decreased activity of MPO and reduced I/R-induced lipid peroxidation, and depleted GSH, SOD, and NO; this finding was in agreement with that of a previous study . The free radical-scavenging/antioxidant properties of TQ may be partly attributable to its metabolite dihydrothymoquinone . Regarding their toxicity, the reported TQ LD50 in rats after intraperitoneal injection was 57.5 mg/kg and after oral ingestion was 794.3 mg/kg  what justifies the low doses found in the gastroprotective effect of this compound.
Carvacrol (2-methyl-5-isopropylphenol) is a phenolic monoterpene present in essential oils produced by numerous aromatic plants, such as Nigella sativa L, Origanum vulgare L, and Thymus vulgaris L [85,86]. Carvacrol showed low toxicity in rats  and is recognized as a safe food additive and flavoring agent in beverages and chewing gum . Carvacrol shows anti-inflammatory activity in vitro , as well as antinociceptive and antioxidant activities . A recent study conducted by Silva and collaborators  evaluated the anti-inflammatory and anti-ulcer activities of carvacrol. Carvacrol (50 mg/kg) reduced paw edema in several models of inflammation (dextran, histamine, and substance P), and ear edema induced by 12-O-tetradecanoylphorbol acetate and arachidonic acid in mice. Furthermore, carvacrol showed healing activity on gastric lesions induced by acetic acid after 14 days of treatment. Acetic acid-induced damage in the gastric ulcer model represents human peptic ulcer disease , and the degree of injury is regulated by multiple factors, such as prostaglandins, growth factors, adherent mucus, nitric oxide, and cytokines . Carvacrol showed healing activity on gastric lesions induced by acetic acid at doses of 25, 50, and 100 mg/kg, which produced lesion reductions of 60%, 91%, and 81%, respectively. These effects of carvacrol may result from the inhibition of inflammatory mediators .
Oliveira and collaborators  evaluated the mechanisms through which carvacrol exerted gastroprotective effects in rodents, and showed that carvacrol (25 mg/kg) showed gastroprotective effects in several mouse and rat models of gastric lesions (absolute ethanol, ethanol-acidified, ischemia and reperfusion, nonsteroidal anti-inflammatory drugs), which were mediated by endogenous prostaglandins, increased mucus production, KATP channel opening, and NO and antioxidant properties. Carvacrol also inhibited COX-2  antioxidant activity and pro-inflammatory cytokine TNF-α production . Therefore, these effects may be important mechanisms through which carvacrol produces anti-inflammatory and ulcer healing effects.
α-Terpineol is a volatile monoterpene alcohol with a slightly sweet odor that is found in the oils of several herbs, such as Pandanus odoratissimus L and Carthamus tinctorius L [97,98]. This monoterpenoid is generally recognized as safe, because the 50% oral lethal dose in rats and mice is over 5,000 mg/kg . Pharmacological studies have shown that α-terpineol possesses anticonvulsant , antinociceptive , and hypotensive  effects. Souza and collaborators  showed that α-terpineol showed gastroprotective activity against ethanol-induced ulcer sat doses of 10, 30, and 50 mg/kg, and also reduced gastric lesions induced by indomethacin at doses of 30 and 50 mg/kg. Pretreatment with indomethacin (10 mg/kg) did not inhibit the gastroprotective action of α-terpineol (50 mg/kg) on ethanol-induced lesions, suggesting that the gastroprotective action of α-terpineol does not involve increased prostaglandin synthesis. Gastric volume, pH, and proton concentration values were not altered by α-terpineol after pylorus ligation, indicating that its gastroprotective action does not involve inhibition of gastric acid secretion. Therefore, the observed gastroprotective effects of α-terpineol probably involve the participation of cytoprotective mechanisms.
Terpinen-4-ol is a cyclic monoterpene that is widely distributed in aromatic plants, and found in essential oil from Zingiber montanum Link ex Dietr. , Zingiber cassumunar Link ex Dietr., Malaleuca alternifolia Cheel , Origanum majorana L , as well as other species. Concerning the toxicity of terpinen-4-ol, there is interest with respect to observed nephrotoxic effects of oils of which terpinen-4-ol is the main constituent. However, the available data do not give clear evidence for such an effect .
Terpinen-4-ol has many pharmacological activities, including anti-inflammation  and hypotension effects . Matsunaga and collaborators  showed that essential oil from the leaves of Cryptomeria japonica D. Don inhibited gastric ulcers induced by several mediators, including HCl/ethanol, HCl/aspirin, water-immersion stress, and pylorus ligation. Among the major components of the essential oil of C. japonica, terpinen-4-ol was found to be the most potent in reducing gastric acid secretion and pepsin activity.
Epoxycarvone (EC) is a monocyclic monoterpene found in the essential oils of some plants such as Carum carvi L  and Kaempferia galangal L . In the study of acute toxicity, the LD50 calculated was 923 mg/kg with confidence interval of 820 to 1037 mg/kg, suggesting low toxic effect .
Previous studies have demonstrated that EC shows activity in the central nervous system , anticonvulsant action  and antibacterial effects against Staphylococcus aureus and Candida albicans . Rocha and collaborators  showed that intraperitoneal administration of epoxy-carvone (300 mg/kg) produced a significant antinociceptive effect in the acetic acid-induced abdominal writhing test and formalin-induced nociception (in the first and second phases) in mice. EC also inhibited the increased vascular permeability provoked by acetic acid, demonstrating interference with acute inflammatory processes.
To evaluate the gastroprotective activity of epoxycarvone, Siqueira and collaborators  studied its effect in models of ulcers induced by ethanol and indomethacin in rats. Epoxycarvone (10 to 50 mg/kg) showed gastroprotective effects in both ulcer models. However, these effects did not involve antisecretory activity or increased synthesis of nitric oxide and prostaglandins.
Elemol, or cyclohexanemethanol, is a nontoxic sesquiterpene (Belsito et al. ) used as a fragrance ingredient in decorative cosmetics, fine fragrances, shampoos, and soaps, as well as in non-cosmetic products such as household cleaners and detergents . Elemol is a major constituent of the essential oil of Maclura pomifera which is used as an insect repellent . Elemol is present in the oil composition of Juniperus saltuaria Rehd & Wils and J. squamata var. fargesii Redh. And Wils, which possess antifungal activity .
According to Matsunaga and collaborators , essential oil from the leaves of Cryptomeria japonica D. Don (EOCJ) shows anti-ulcer activity, and significantly decreases gastric lesions in the HCl/ethanol, HCl/aspirin, water-immersion stress, and pylorus ligation models. Compounds with anti-ulcer activity were separated from EOCJ by use of distillation and chromatography, and terpinen-4-ol and elemol were isolated as active compounds.
Nerolidol (3,7,11-trimethyl-1,6,10-dodecatrien-3-ol) is a natural aliphatic sesquiterpene alcohol that is an important component of essential oils from many plants [123,124], and is approved by the U.S. Food and Drug Administration as a food flavoring agent .
Klopell and collaborators  studied the anti-ulcer activity of Baccharis dracunculifolia DC essential oil and its main constituent nerolidol using the ethanol-induced model of acute gastric lesions. Ulcerative lesions in the indomethacin- and stress-induced ulcer models were reduced by oral administration of the essential oil of B. dracunculifolia (50–500 mg/kg) or nerolidol (50–500 mg/kg). In agreement with previous reports, Massignani and collaborators  reported that the essential oil obtained from the aerial parts of B. dracunculifolia significantly diminished (at doses of 50 mg/kg and 500 mg/kg) total lesion area, lesion occurrence, and the volume and acidity of gastric juice in the ethanol-, indomethacin-, and stress-induced ulcer models, and significantly increased gastric pH in the pylorus ligation model. Phytochemical analyses carried out on B. dracunculifolia essential oil indicated that nerolidol (23.58%) could be the constituent primarily responsible for its anti-ulcer activity.
(‒)-α-Bisabolol, is a natural, unsaturated, monocyclic sesquiterpene alcohol found in the oils of Matricaria chamomilla L, Vanillosmopsis erythropappa Schult. Bip., and other plants . The oral acute toxicity (LD50) of (‒)-α-bisabolol in mice was 5.1 mL/kg body weight and 14.9 mL/kg for ras . From this data it is possible to conclude that the bisabolol is safe.
This sesquiterpenoid compound is used as a fragrance ingredient in decorative cosmetics, fine fragrances, shampoos, toilet soaps, and household cleaners . (‒)-α-Bisabolol and its oxidized metabolites are used as marker compounds for distinguishing different chemotypes. These compounds produce the aroma of the essential oil of M. chamomilla and contribute to its therapeutic properties . Many authors have suggested that (‒)-α-bisabolol possesses a variety of biological activities, including anti-fungal , antinociception  and antitumor effects .
Leite and collaborators  showed gastroprotective effects exerted by essential oil from the bark of Vanillosmopsis arborea Baker, of which (‒)-α-bisabolol is a major component, at doses of 200 and 400 mg/kgin a model of ethanol-induced lesions in mice. Subsequently, Bezerra and collaborators  demonstrated that animals orally treated with Matricaria recutita L extract (200 and 400 mg/kg) or (‒)-α-bisabolol (50 and 100 mg/kg) were protected from damage caused by ethanol with effectiveness of 78%–96%. In mechanistic studies, the gastroprotective effect of (‒)-α-bisabolol (100 mg/kg) was reversed when the animals were pretreated with glibenclamide (a KATP channel blocker), suggesting a role of endogenous prostaglandins in its gastroprotective activity .
Aiming to expand gastroprotective studies with (‒)-α-bisabolol, Rocha and collaborators  investigated the anti-ulcer activity of this terpene in the indomethacin- and alcohol-induced ulcer model in mice, and the mechanisms involved in this effect. (−)-α-bisabolol (100 and 200 mg/kg) was effective in protecting the gastric mucosa against lesions induced by ethanol and indomethacin when compared to the control group. When animals in the ethanol injury model were pretreated with indomethacin, glibenclamide, or L-NAME (a non-selective competitive inhibitor of NOS), there was no change in the effect produced by (‒)-α-bisabolol (200 mg/kg), suggesting that this effect was not mediated by prostaglandins, nitric oxide, or KATP.
The literature reports that endogenous non-protein sulfhydryl (NP-SH) compounds are important mediators of gastric mucosa protection in models of gastric lesions induced by ethanol and indomethacin [50,135]. (‒)-α-Bisabolol (200 mg/kg) prevented the depletion of GSH promoted by ethanol and indomethacin, which may be associated with its antioxidant properties. ROS have also been shown to play a critical role in gastric ulceration induced by ethanol and NSAIDs. Therefore, enzymatic and non-enzymatic antioxidant defenses play an important role in the prevention of gastric damage. In this context, Rocha and collaborators  investigated the antioxidant effect of (‒)-α-bisabolol using an ethanol-induced injury model to better characterize its antioxidant mechanisms. MDA is the final product of lipid peroxidation and is used to determine lipid peroxidation levels in tissues . Ethanol causes necrotic lesions of the gastric mucosa in a multifactorial manner. These effects are probably due to biological actions, such as lipid peroxidation, free radical formation, oxidative stress, and changes in permeability . Organisms have enzymatic and non-enzymatic defenses against ROS-induced lipid peroxidation, including GSH, SOD, and GSH-px . Ethanol has been shown to markedly increase MDA level, an index of lipid peroxidation, which is accompanied by a decrease in GSH, SOD, and GSH-px, which are endogenous antioxidants . (‒)-α-Bisabolol prevented the increase in MDA induced by ethanol, increased SOD activity, and reduced CAT activity. However, this activity does not seem to involve the participation of nitric oxide. Recently, (−)-α-bisabolol showed anti-inflammatory and antinociceptive activity by decreasing leukocyte migration, protein extravasation, and TNF-α levels in a model of carrageenan-induced peritonitis in mice . These findings support the gastroprotective activity of (‒)-α-bisabolol, because ethanol-induced lesions have the characteristic of inducing inflammatory neutrophil migration in gastric lesions, leading to activation of the pro-inflammatory cascade .
Anethole (1-methoxy-4-(1-propenyl)-benzene) is an aromatic compound largely used in industry as a flavor agent in food and alcoholic beverages. Anethole also possesses anti-inflammatory  and anesthetic activities . Freire and collaborators  determined the antioxidant, anti-inflammatory, and gastroprotective activity of anethole and hydroxylated derivatives. In the DPPH model, which assesses the inhibitory activity of free radicals generated during lipid peroxidation , as well as the acetic acid-induced vascular permeability model, anethole derivatives (300 mg/kg) showed antioxidant and anti-inflammatory activity. These results show the correlation between the antioxidant and anti-inflammatory activities of anethole derivatives, in addition to the presence of phenolic groups that act as antioxidants, due to their ability to scavenge free radicals associated with various human diseases . To assess the gastroprotective effects of anethole and derivatives, these compounds were investigated in the ethanol-induced ulcer model in mice. Anethole (300 mg/kg) increased the level of gastric mucus, while derivatives (300 mg/kg) showed gastroprotective activity without affecting mucus secretion. This result indicates that the double bond and polar group in the side chain of anethole increase gastroprotective activity, but reduce activity on mucus secretion .
Croton zehntneri Pax et Hoff (Euphorbiaceae) is a bush native to northeast Brazil, where it is commonly known as “canela de cunhã” and “canela de cheiro” . Preliminary findings have demonstrated that the leaves of C. zehntneri have a rich essential oil content, and one of its principal characteristics is a strong and pleasant odor reminiscent of anise and clove . Anethole is a principal constituent of the essential oil of Croton zehntneri (EOCZ), which is used therapeutically in popular folk medicine in a variety of situations, including the relief of pain and anxiety, and for the treatment of gastrointestinal disturbances . Coelho-de-Souza  demonstrated that oral treatment with EOCZ and its main constituent anethole at doses of 30, 100, and 300 mg/kg, caused gastroprotection against ethanol- and indomethacin-induced gastric damage. Moreover, neither EOCZ nor anethole reduced the lesion index in cold-restraint stress-induced ulcers in rats. These studies also revealed that pretreatment with EOCZ and anethole (30 and 300 mg/kg) significantly increased mucus production by the gastric mucosa in the ethanol-induced ulcer model. The mechanism of gastroprotection of EOCZ and anethole, at the same doses, seemed not to be related to effective participation of endogenous sulfhydryl groups or on antisecretory effects in pylorus-ligated rats.
Regarding to its toxicity, anethole was examined in some sub-chronic toxicity studies in rats. The only effects observed were slight hepatic changes in the high dose groups (500–700 mg/kg body weight) [149,150]. These observations have been corroborated by  that investigated the effect of anethole in a chronic feeding study carried out in rats at concentrations of 0%, 0.25%, 0.5% and 1% for 117–121 wk. The results showed that anethole does not constitute a significant carcinogenic risk to man .
Eugenol is a phenylpropanoid and a major constituent of the essential oil of Syzygium aromaticum L, a plant commonly known as “cravo da india” that possesses several medicinal properties, including use as an antiseptic and analgesic in dental care, where the undiluted oil may be rubbed on the gums to treat toothache . The LD50 for eugenol, administered to rats by oral route was estimated to be 1.93 g/kg  and to mice was 3,000 mg/kg . Taken together these data show that this compound has low toxicity and may serve to guide to safe dosage in man.
Santin and collaborators  investigated the gastroprotective effects of eugenol in different animal models, and demonstrated that eugenol (100 and 250 mg/kg) reduced ethanol-induced gastric lesions (72% and 95%, respectively) compared to the control group. In the indomethacin-induced ulcer model, eugenol (50 and 250 mg/kg) significantly reduced incidence of ulcers. Furthermore, eugenol (250 mg/kg) did not affect secretion or gastric parameters (volume of gastric juice and acidity) in the pylorus ligation model, which suggests that the gastroprotective action of this substance is not related to antisecretory effects. Eugenol (100 and 250 mg/kg) increased the production of gastric mucus compared to the control group. The most likely mechanism of eugenol gastroprotection is related to factors that increase mucus production and barrier resistance . In an attempt to determine the gastroprotective mechanism of action of eugenol, we assessed the involvement of endogenous nitric oxide and participation of endogenous sulfhydryl, but results showed that the effect of eugenol is not associated with nitric oxide activity or increased endogenous SH. Capasso and collaborators  showed that eugenol exhibited dose-dependent gastroprotection (10 to 100 mg/kg) in models of ethanol-induced injury, and by PAF, a derived from platelet membrane, involved in pathophysiology of different pathological processes, such as gastric ulcer  and associated with changes in gastric mucosa of rats treated with ethanol .
In an attempt to identify the gastroprotective mechanism of eugenol, Morsy and collaborators  evaluated the effect of this phenylpropanoid in the indomethacin-induced gastric ulcer model in rats. The inhibition of prostaglandins by NSAIDs induces neutrophil infiltration, imbalances nitric oxide concentrations , increases lipid peroxidation with increased production of reactive oxygen species, and decreases the activity of glutathione peroxidase . Morsy and collaborators  showed that pretreatment with eugenol (100 mg/kg)in the indomethacin-induced ulcer model in rats reduced gastric ulcers, gastric acid secretion, and pepsin activity, and increased the concentration of gastric mucin. Endogenous gastric pepsin has an important role in the pathogenesis of gastric ulcers; the accumulation of gastric acid and pepsin leads to self-digestion of the gastric mucosa . Mucin is synthesized and secreted immediately after gastric mucosal damage induced by drugs and parasites, and plays a prominent role in the recovery of injured gastric mucosa . The effects of eugenol may be due to its antisecretory properties and to opening of KATP channels. Eugenol also reduced levels of MDA and nitrite, and prevented the depletion of reduced glutathione, indicating antioxidant action.
Confirming previous findings, Jung and collaborators  demonstrates that eugenol isolated from Cinnamomum cassia Nees ex Blume showed antioxidant activity in vitro in the DPPH model. Using ascorbic acid (IC50 < 1 μg/mL) as a reference value, eugenol showed significant antioxidant activity (IC50 < 9 μg/mL). It is known that damage to gastric cells in acute and chronic inflammation is due to the toxicity of reactive oxygen species generated in the stomach, so ROS play an important role in the progression of gastric ulcers. Eugenol also demonstrated cytotoxic effects on H. pylori, with inhibition at about 8.2 mg/mL, which was comparable to reference drug ampicillin, which showed inhibition at 10 g/mL.
The ethanol induction model of gastric lesions is widely used in the investigation of anti-ulcer drugs. Lesions in this model are associated with increased production of ROS, with consequent increased lipid peroxidation, decreased mucus production, and bicarbonate secretion . The participation of HCl causes severe damage to the gastric mucosa, accelerating the injury process . Mice treated with eugenol showed dose-dependent reduction of lesions, with 65% inhibition at a dose of 100 mg/kg, which was greater than that produced by cimetidine, but eugenol did not alter secretion parameters in the gastric pylorus ligation model in Sprague Dawley rats. The authors also assessed the effect of eugenol on mucus secretion in the ethanol induction model of gastric lesions, and found that eugenol (100 mg/kg) increased the content of mucus (183.5 mg, compared to 173.9 mg for the saline control group). These results show that eugenol has gastroprotective antioxidant activity, neutralizes acid secretion, and partially inhibits H. pylori, and is therefore a potential candidate for treatment of gastritis.
2.15. 1′S-1′-Acetoxychavicol and 1′S-1′-Acetoxyeugenol Acetate
Alpinia galanga (L.) Willd, known as galangal, is widely cultivated in China, India, and Southeast Asia. The rhizomes of galangal are widely used as spice or ginger substitutes for flavoring foods, and in traditional medicine . In chemical studies of A. galanga, the principal compound, 1'S-1'-acetoxychavicol acetate, was reported to possess various biological activities, among them anti-inflammatory , antioxidant , and anti-ulcer properties . Matsuda and collaborators  described the protective effect of 1'S-1'-acetoxychavicol and some related phenylpropanoids from the rhizomes of A. galangal on gastric lesions induced by several necrotizing agents, and found that 1'S-1'-acetoxychavicol and 1'S-1'-acetoxyeugenol acetate (2.0 mg/kg) inhibited ethanol-induced gastric mucosal lesions. In addition, 1'S-1'-acetoxychavicol acetate inhibited lesions induced by 0.6 M HCl and aspirin, but did not show a significant effect on indomethacin-induced gastric lesions or acid output in pylorus-ligated rats at doses of 0.5–5.0 mg/kg. The anti-ulcer effects of 1′S-1′-acetoxychavicol acetate were attenuated by pretreatment with indomethacin and N-ethylmaleimide (an SH blocker on sulfhydryl compounds), and 1'S-1'acetoxychavicol acetate significantly increased glutathione levels ingastric mucosa in rats. These findings indicate a strong participation of endogenous prostaglandins and sulfhydryl compounds in the gastroprotective effect of 1'S-1'-acetoxychavicol acetate.
Cinnamaldehyde (CA) is a major component of cinnamon, a popular spice that has been used in traditional medicine for its antimicrobial and anti-inflammatory effects, in the treatment of diabetes [175,176], and more recently in preventing lipid peroxidation .
Mereto and collaborators , using Sprague-Dawley rats found that high doses of CA (500 mg/kg, p.o.) for 14 successive days produced a modest but statistically significant genetic alterations at the chromosomal level in the liver, and suggest that the liver is the preferential target of its undesirable effects.
CA is known to have a wide range of biological properties, such as anti-candidal , anti-inflammatory [180,181], and anti-oxidative activities , as well as important actions in the cardiovascular system, including vasorelaxation and decreases in blood pressure associated with diabetes .
Only one study has shown the gastroprotective activity of cinnamon in mice. Tankam and collaborators  found that a cinnamon powder diet (100 mg cinnamon powder per gram of food for 4 weeks) significantly protected mice against ulceration by stress, ethanol, HCl, and oral administration of aspirin, but not against ulceration induced by indomethacin. These findings suggest that regular ingestion of cinnamon offers gastroprotection through a cytoprotective mechanism, and that the active compound of cinnamon powder for gastroprotective activity is probably cinnamaldehyde. This result is consistent with earlier studies which reported that cinnamaldehyde has antiulcer activity [185,186].
2.17. Cinnamic Acid
Cinnamic acid (Ci), an active ingredient in cinnamon and propolis (used by honeybees as a hive sealant), has shown a variety of pharmacological properties. Concerning its oral acute toxicity, the LD50 values have been reported for 4,454 mg/kg bw in rats  and >5,000 mg/kg to mice , demonstrating that the oral acute toxicity of these cinnamyl derivatives is extremely low.
Conti and collaborators  demonstrated that Ci inhibited TNF-α and IL-10 production by human monocytes by blocking Toll-like receptors (TLR-4), a major class of the pattern-recognition receptors (PRRs) that are present on immune cells, which are involved in the induction of inflammation in intestinal epithelial cells . Ci at a concentration of 1 mM significantly inhibited the formation of advanced glycation end products (AGEs). Furthermore, Ci reduced fructosamine levels, and prevented oxidative protein damage, including effects on protein carbonyl formation. These findings suggest that Ci has an antidiabetic effect .
In a study on protection against ulcer and gastritis by Cinnamomi ramulus Nees ex Blume (CR, Cinnamomum cassia) extract and cinnamic acid, Jung and collaborators , demonstrated that CR ethanolic extract showed potent antioxidant activity, acid-neutralizing capacity, and cytotoxicity against Helicobacter pylori. Likewise, cinnamic acid (100 mg/kg) significantly inhibited (42.8%) HCl/ethanol-induced gastric lesions and increased mucus content in rats. Ci (IC50> 300 µg/mL), which was isolated from CR, exhibited low antioxidant activity in vitro and protective effects against gastric damage in vivo through stimulation of mucus secretion. Taken together, these data suggest that CR and cinnamic acid show potential as gastroprotective agents.
Citral is a β-substituted vinyl aldehyde that occurs naturally in several plant species, including myrtle trees, African basil, lemons, limes and oranges . Because of its lemon flavor and odor, citral is used as a flavoring and fragrance agent in foods and cosmetics and is recognized as safe .
Work carried out by Ortiz and collaborators  shows that the gastric injury produced by naproxen (100 mg/kg, p.o.) was able to produce significant gastric injury by the 3 h time-point. Nevertheless the highest doses of combined naproxen and citral (136.4 and 287.4 mg/kg, p.o., respectively) produced less gastric injury than naproxen alone. These data suggest that the naproxen-citral combination interacts at the systemic level, produces minor gastric damage, and potentially has therapeutic advantages for the clinical treatment of inflammatory pain.
Thymol, a monocyclic monoterpene compound isolated from Thymus vulgaris L or Origanum vulgare spp., has been widely used in the pharmaceutical industry . This substance is listed by the US Food and Drug Administration (US-FDA) as a food additive on the “generally recognized as safe” (GRAS) list and therefore it would be considered nontoxic. Previous studies have demonstrated that thymol has anti-bacterial and anti-inflammatory properties [196,197].
Recently, Dhaneshwar and collaborators  developed a co-drug of diacerein with thymol. Diacerein is a symptomatic slow acting disease modifying IL-1b inhibitor, known to possess antiarthritic and moderate anti-inflammatory activity . The data obtained shown that chemical linkage of thymol with diacerein improved its bioavailability. The results of ulcerogenic activity, by using the Rainsford’s cold stress model, revealed that diacerein when directly administered orally, showed higher ulcer index (ulcer index: 6.03 ± 0.15), whereas the association diacerin thimol exhibited lower ulcerogenic potential (4.17 ± 1.03) in rats. In Rainsford’s cold stress model there is involvement of the parietal and zymogen cells than is evident after aspirin treatment alone (which leads to mucosal erosions but not ulceration per se). Since the physical stress conditions employed mimic the responses in the stomach following psychological stress, the combined aspirin plus stress treatment may serve as a useful model for studying gastric ulcerogenesis representative of that in humans .
Bisabolangelone (BISA), a sesquiterpene found in the species from the Umbelliferae Family. BISA shows anti-ulcer and anti-inflammatory [201,202] and recently, in a molecular studies, Kim and collaborators  have shown that BISA suppressed MAPK phosphorylation and nuclear translocation of NF-jB p50/p65 suggesting that BISA works by blocking MAPK and NF-jB signaling, confirming that BISA possesses anti-inflammatory properties.
Angelica polymorpha Maxim, is a herbal medicine (Umbelliferae) which was popularly used to treat gastric ulcer [204,205]. Several coumarin, monoterpene, and sesquiterpene such as BISA have been reported as biologically active constituents [206,207,208].
Wang and collaborators (2009) , evaluated the anti-ulcer effects of BISA from A. polymorpha Maxim in ethanol-induced gastric lesion and pylorus ligation in mouse and rats, respectively. The results showed that BISA (3.8, 7.6 and 15.3 mg/kg body weight) produced a significant reduction of the lesion. The extent of inhibitions for the respective doses employed was 64%, 75% and 82%, respectively. In pylorus ligated model, BISA (3.8 to 15.3 mg/kg) significantly inhibited the activity of H+/K+-ATPase, reduced the volume of gastric juice, raised the pH value of gastric juice, but had no effect on the activity of the pepsase. Taken all together the findings indicate that BISA operates by inhibiting the activity of the H+/K+-ATPase, then reducing the secretion of H+.
The literature shows that there is limited clinical data available to support the use of herbs as gastroprotective/antiulcer agents and thus, the studies on efficacy and safety are limited. Despite this, there are several botanical products with potential therapeutic applications because of their high efficacy and low toxicity. This review shows that terpenes and phenylpropanoids present in many essential oils have potential for use in peptic ulcer disease. Among the bioactive constituents of essential oils, there are several chemical classes, such as alcohol, phenol, aldehyde, carboxylic acid, ether, quinone and bifunctional molecules. The different experimental conditions, doses, and animals used in testing, not possible to establish a structure-activity relationship in this review. However, the same feature of these molecules is that they are low molecular weight compounds. The anti-ulcer activity of these natural products can be attributed to several mechanisms, such as free-radical scavenging, inhibition of acid secretion, activity against H. pylori, and strengthening of the gastric mucosal barrier.
These findings reinforce the importance and usefulness of constituents of essential oils as promising agents in the management of gastric ulcers, a global disease in which there is high unmet needs related to current treatments in terms of efficacy, safety and low cost.
Possible mechanisms of action from essential oils constituents with anti-ulcer activity (Figure S1); Essential oil constituents with anti-ulcer activity (Table S1), can be accessed at: http://www.mdpi.com/1420-3049/19/5/5717/s1.
Cyclic adenosine monophosphate
Hydrogen potassium ATPase
Heat shock protein 70
ATP-sensitive potassium channel
N (G)-nitro-L-arginine methyl ester
Minimum inhibitory concentration
Nitric oxide synthase
Nonsteroidal anti-inflammatory drugs
Potential of hydrogen
Reactive oxygen species
Tumor necrosis factoralpha
Vasoactive intestinal peptide
This research was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
Francisco was responsible for writing the pharmacological part of the manuscript. Luciana and Élida did the survey data in the database and will format the manuscript. Damião wrote the chemical part and revised the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
- Zapata-Colindres, J.C.; Zepeda-Gómez, S.; Montaño-Loza, A.; Vázquez-Ballesteros, E.; de Jesús Villalobos, J.; Valdovinos-Andraca, F. The association of Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs in peptic ulcer disease. Can. J. Gastroenterol. 2006, 20, 277–280. [Google Scholar]
- Marcus, E.A.; Vagin, O.; Tokhtaeva, E.; Sachs, G.; Scott, D.R. Helicobacter pylori impedes acid-induced tightening of gastric epithelial junctions. Am. J. Physiol. Gastrointest. Liver Physiol. 2013, 305, G731–G739. [Google Scholar] [CrossRef]
- Prabhu, V.; Shivani, A. An overview of history, pathogenesis and treatment of perforated peptic ulcer disease with evaluation of prognostic scoring in adults. Ann. Med. Health Sci. Res. 2014, 4, 22–29. [Google Scholar] [CrossRef]
- Klein, L.C., Jr.; Gandolfi, R.B.; Santin, J.R.; Lemos, M.; Cechinel-Filho, V.; Andrade, S.F. Antiulcerogenic activity of extract, fractions, and some compounds obtained from Polygala cyparissias St. Hillaire & Moquin (Poligalaceae). Naunyn-Schmiedeberg’s Arch. Pharmacol. 2010, 381, 121–126. [Google Scholar] [CrossRef]
- Behrman, S.W. Management of complicated peptic ulcer disease. Arch. Surg. 2005, 140, 201–208. [Google Scholar] [CrossRef]
- Lockrey, G.; Lima, L. Peptic ulcer disease in older people. J. Pharm. Pract. Res. 2011, 41, 58–61. [Google Scholar]
- Gadekar, R.; Singour, P.K.; Chaurasiya, P.K.; Pawar, R.S.; Patil, U.K. A potential of some medicinal plants as an antiulcer agents. Pharmacogn. Rev. 2010, 4, 136–146. [Google Scholar] [CrossRef]
- Malfertheiner, P.; Chan, F.K.; Mccoll, K.E. Peptic ulcer disease. Lancet 2009, 374, 1449–1461. [Google Scholar] [CrossRef]
- Awaad, A.S.; El-Meligy, R.M.; Soliman, G.A. Natural products in treatment of ulcerative colitis and peptic ulcer. J. Saudi Chem. Soc. 2013, 17, 101–124. [Google Scholar] [CrossRef]
- Lakshimi, V.; Singh, N.; Shrivastva, S.; Mishra, S.K.; Dharmani, P.; Palit, G. Gedunin and photogedunin of Xylocarpus granatum show significant anti-secretory effects and protect the gastric mucosa of peptic ulcer in rats. Phytomedicine 2009, 17, 569–574. [Google Scholar]
- Sheen, E.; Triadafilopoulos, G. Adverse effects of long-term proton pump inhibitor therapy. Dig. Dis. Sci. 2011, 56, 931–950. [Google Scholar] [CrossRef]
- Zayachkivska, O.S.; Konturek, S.J.; Drozdowicz, D.; Brzozowski, T.; Gzhegotsky, M.R. Influence of plant-originated gastroprotective and antiulcer substances on gastric mucosal repair. Fiziol. Zh. 2004, 50, 118–127. [Google Scholar]
- Schmeda-Hirschmann, G.; Yesilada, E. Traditional medicine and gastroprotective crude drugs. J. Ethnopharmacol. 2005, 22, 61–66. [Google Scholar]
- Edris, A.E. Pharmaceutical and therapeutic potentials of essential oils and their individual volatile constituents: A review. Phytother. Res. 2007, 21, 308–323. [Google Scholar] [CrossRef]
- De Sousa, D.P. Medicinal Essential Oils: Chemical, Pharmacological and Therapeutic Aspects, 1st ed.; Nova Science Publishers: New York, NY, USA, 2012; pp. 1–236. [Google Scholar]
- Bakkali, F.; Averbeck, S.; Averbeck, D.; Idaomar, M. Biological effects of essential oils—A review. Food Chem. Toxicol. 2008, 46, 446–475. [Google Scholar] [CrossRef]
- Lewis, D.A.; Hanson, P.J. Anti-ulcer drugs of plant origin. Prog. Med. Chem. 1991, 28, 201–231. [Google Scholar] [CrossRef]
- Rozza, A.L.; Hiruma-Lima, C.A.; Takahira, R.K.; Padovani, C.R.; Pellizzon, C.H. Effect of menthol in experimentally induced ulcers: Pathways of gastroprotection. Chem. Biol. Interact. 2013, 206, 272–278. [Google Scholar] [CrossRef]
- Shah, K.; Shrivastava, S.; Mishra, P. Evaluation of mefenamic acid mutual prodrugs. Med. Chem. Res. 2013, 22, 70–77. [Google Scholar] [CrossRef]
- Kamatou, G.P.; Vermaak, I.; Viljoen, A.M.; Lawrence, B.M. Menthol: A simple monoterpene with remarkable biological properties. Phytochemistry 2013, 96, 15–25. [Google Scholar] [CrossRef]
- Shanbhag, V.R.; Rider, A.M.; Gokhale, R.; Harpalanai, A.; Dick, R.M. Ester and amide prodrugs of ibuprofen and naproxen: Synthesis, anti-inflammatory activity and gastrointestinal toxicity. J. Pharm. Sci. 1992, 81, 149–154. [Google Scholar] [CrossRef]
- Khan, M.S.Y.; Akhter, M. Synthesis, pharmacological activity and hydrolytic behavior of glyceride prodrugs of ibuprofen. Eur. J. Med. Chem. 2005, 40, 371–376. [Google Scholar] [CrossRef]
- Redasani, V.K.; Sanjay, B.B. Synthesis and evaluation of mutual prodrugs of ibuprofen with menthol, thymol and eugenol. Eur. J. Med. Chem. 2012, 56, 134–138. [Google Scholar] [CrossRef]
- Santos, F.A.; Rao, V.S.N. 1,8-Cineol, a food flavoring agent, prevents ethanol-induced gastric injury in rats. Digest. Dis. Sci. 2001, 46, 331–337. [Google Scholar] [CrossRef]
- Vernin, G.A.; Parkanyi, C.; Cozzolino, F.; Fellous, R. GC/MS analysis of the volatile constituents of Corymbia citriodora Hook. from Réunion Island. J. Essent. Oil Res. 2004, 16, 560–565. [Google Scholar] [CrossRef]
- Paik, S.Y.; Kok, K.H.; Beak, S.M.; Paek, S.H.; Kim, J.A. The essential oils from Zanthoxylum schinifolium pericarp induce apoptosis of HepG2 human hepatoma cells through increased production of reactive oxygen species. Biol. Pharm. Bull. 2005, 28, 802–807. [Google Scholar] [CrossRef]
- Serra, S.; Brenna, E.; Fuganti, C.; Maggioni, F. Lipase-catalyzed resolution of p-menthan-3-ols monoterpenes: Preparation of the enantiomer-enriched forms of menthol, isopulegol, trans- and cis-piperitol, and cis-isopiperiten. Tetrahedron Asymmetry 2003, 14, 3313–3319. [Google Scholar] [CrossRef]
- Bhatia, S.P.; McGinty, D.; Letizia, C.S.; Api, A.M. Fragrance material review on alpha-bisabolol. Food Chem. Toxicol. 2008, 46, 72–76. [Google Scholar] [CrossRef]
- Bhatia, S.P.; McGinty, D.; Letizia, C.S.; Api, A.M. Fragrance material review on isopulegol. Food Chem. Toxicol. 2008, 46, 185–189. [Google Scholar] [CrossRef]
- Spindler, P.; Madsen, C. Subchronic toxicity study of peppermint oil in rats. Toxicol. Lett. 1992, 62, 215–220. [Google Scholar] [CrossRef]
- Silva, M.I.G.; Moura, B.A.; Neto, M.R.A.; Tomé, A.R.; Rocha, N.F.M.; Carvalho, A.M.R; Macêdo, D.S.; Vasconcelos, S.M.M.; Sousa, D.P.; Viana, G.S.B.; et al. Gastroprotective activity of isopulegol on experimentally induced gastric lesions in mice: Investigation of possible mechanisms of action. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2009, 380, 233–245. [Google Scholar] [CrossRef]
- Robert, A. Cytoprotection by prostaglandins. Gastroenterology 1979, 77, 761–767. [Google Scholar]
- Das, S.K.; Vasudevan, D.M. Alcohol-induced oxidative stress. Life Sci. 2007, 81, 177–187. [Google Scholar] [CrossRef]
- Szabo, S. Mechanisms of Mucosal Injury in the Stomach and Duodenum: Time-sequence Analysis of Morphologic, Functional, Biochemical and Histochemical Studies Scandinavian. J. Gastroenterol. 1987, 22, 21–28. [Google Scholar]
- Nguemfo, E.L.; Dimo, T.; Dongmo, A.B.; Azebaze, A.G.; Alaoui, K.; Asongalem, A.E.; Cherrah, Y.; Kamtchouing, P. Anti-oxidative and anti-inflammatory activities of some isolated constituents from the stem bark of Allanblackia monticola Staner L.C (Guttiferae). Inflammopharmacology 2009, 17, 37–41. [Google Scholar] [CrossRef]
- Miller, T.A. Protective effects of prostaglandins against gastric mucosal damage: Current knowledge and proposed mechanisms. Am. J. Physiol. 1983, 245, 601–623. [Google Scholar]
- Rainsford, K.D. Structure-activity relationships of non-steroid anti-inflammatory drug gastric ulcerogenic activity. Agents Actions 1978, 8, 587–605. [Google Scholar] [CrossRef]
- Wallace, J.L. Nitric oxide, aspirin-triggered lipoxins and NO aspirin in gastric protection. Inflamm. Allergy Drug Targets 2006, 5, 133–137. [Google Scholar] [CrossRef]
- Peskar, B.M.; Ehrlich, K.; Peskar, B.M. Role of ATP-Sensitive Potassium Channels in Prostaglandin-Mediated Gastroprotection in the Rat. J. Pharmacol. Exp. Ther. 2002, 301, 969–974. [Google Scholar] [CrossRef]
- Sayyah, M.; Nadjafnia, L.; Kamalinejad, M. Anticonvulsant activity and chemical composition of Artemisia dracunculus L. essential oil. J. Ethnopharmacol. 2004, 94, 283–287. [Google Scholar] [CrossRef]
- Meral, G.E.; Konyalioglu, S.; Ozturk, B. Essential oil composition and antioxidant activity of endemic Ziziphora taurica subsp. cleonioides. Fitoter 2002, 73, 716–718. [Google Scholar] [CrossRef]
- Siani, A.C.; Garrido, I.S.; Monteiro, S.S.; Carvalho, E.S.; Ramos, M.F.S. Protium icicariba as a source of volatile essences. Biochem. Syst. Ecol. 2004, 32, 477–489. [Google Scholar] [CrossRef]
- Amaral, M.P.M.; Braga, F.A.V.; Passos, F.F.B.; Almeida, F.R.C.; Oliveira, R.C.M.; Carvalho, A.A.; Arruda, D.; Alexandri, F.D.; Katzin, A.; Uliana, S. Antileishmanial activity of the terpene Nerolidol. Clin. Exp. Pharmacol. Physiol. 2005, 49, 1679–1687. [Google Scholar]
- Sun, J. D-Limonene: Safety and clinical applications. Altern. Med. Rev. 2007, 12, 259–264. [Google Scholar]
- Moraes, T.M.; Kushima, H.; Moleiro, F.C.; Santos, R.C.; Rocha, L.R.M.; Marques, M.O.; Vilegas, W.; Hiruma-Lima, C.A. Effects of limonene and essential oil from Citrus aurantium on gastric mucosa: Role of prostaglandins and gastric mucus secretion. Chem. Biol. Interact. 2009, 180, 499–505. [Google Scholar] [CrossRef]
- Rozza, A.L.; Moraes, T.M.; Kushima, H.; Tanimoto, A.; Marques, M.O.M.; Bauab, T.M.; Hiruma-Lima, C.A.; Pellizzon, C.H. Gastroprotective mechanisms of Citrus lemon (Rutaceae) essential oil and its majority compounds limonene and β-pinene: Involvement of heat-shock protein-70, vasoactive intestinal peptide, glutathione, sulfhydryl compounds, nitric oxide and prostaglandin E2. Chem. Biol. Interact. 2011, 189, 82–89. [Google Scholar] [CrossRef]
- Baananou, S.; Bouftira, I.; Mahmoud, A.; Boukef, K.; Marongiu, B.; Boughattas, N.A. Antiulcerogenic and antibacterial activities of Apium graveolens essential oil and extract. Nat. Prod. Res. 2013, 27, 1075–1083. [Google Scholar] [CrossRef]
- Al Moutaery, A.R. Protective effect of ketoconazole against experimentally induced gastric ulcers in rats. Res. Commun. Mol. Pathol. Pharmacol. 2003, 113, 5–23. [Google Scholar]
- Tunçel, N.; Tunçel, M.; Aboul-Enein, H.Y. Effects of the vasoactive intestinal peptide on stress-induced mucosal ulcers and modulation of methylation of histamine in gastric tissue of the rats. Il Farmaco 2003, 58, 449–454. [Google Scholar] [CrossRef]
- Szabo, S.; Vattay, P. Experimental gastric and duodenal ulcers. Advances in pathogenesis. Gastroenterol. Clin. N. Am. 1990, 19, 67–85. [Google Scholar]
- Muhammad, J.S.; Sugiyama, T.; Zaidi, S.F. Gastric pathophysiological ins and outs of helicobacter pylori: A review. J. Pak. Med. Assoc. 2013, 63, 1528–1533. [Google Scholar]
- Alarcon, T.; Domingo, D.; Lopez-Brea, M. Antibiotic resistance problems with Helicobacter pylori. Int. J. Antimicrob. Agents 1999, 12, 19–26. [Google Scholar] [CrossRef]
- Mitscher, L.A.; Drake, S.; Gollapudi, S.R.; Okwute, K. Model look at folkloric use of anti-infective agents. J. Nat. Prod. 1987, 50, 1025–1040. [Google Scholar] [CrossRef]
- Sanguinetti, E.E. Plantas Que Curam, 2nd ed.; Editora Rígel: Porto Alegre, RS, Brazil, 1989; p. 208. [Google Scholar]
- Bandhopadhyay, U.; Biswas, K.; Chatterjee, R.; Kumar Ganguly, I.C.C.; Bhattacharya, K.; Banerjee, R. Gastroprotective effect of Neem (Azadiracta indica) bark extract: Possible involvement of H+K+ATPase inhibition and scavenging of hydroxyl radical. Life Sci. 2002, 71, 2845–2865. [Google Scholar] [CrossRef]
- Martin, G.R.; Wallace, J.L. Gastrointestinal inflammation: A central component of mucosal defense and repair. Exp. Biol. Med. 2006, 231, 130–137. [Google Scholar]
- Rainsford, K.D. The effect of 5-lipoxygenase inhibitors and leukotriene antagonists on the development of gastric lesions induced by non steroidal anti-inflammatory drugs in mice. Agents Action 1987, 21, 316–319. [Google Scholar] [CrossRef]
- Glavin, G.B.; Szabo, S. Experimental gastric mucosal injury, laboratory models reveal mechanism of pathogenesis and new therapeutic strategies. FASEB J. 1992, 6, 825–831. [Google Scholar]
- Breggia, M.E.; Miguenz, M.; Silberman, P.E.; Laudisi, C.; Lemberg, A.; Filinger, E. Fármacos usados para el Control de la Acidez Gástrica y el Tratamiento de la Úlcera Péptica. Acta Farmacéut. Bonaer. 2009, 19, 133–142, (In Spanish). [Google Scholar]
- Flemstrom, G.; Isenberg, J.I. Gastroduodenal mucosal alkaline secretion and mucosal protection. News Physiol. Sci. 2001, 16, 23–28. [Google Scholar]
- Tariq, M.; Khan, H.A.; Elfaki, I.; Arshaduddin, M.; Al Moutaery, M.; Al Rayes, H.; Al Swailam, R. Gastric antisecretory and antiulcer effects of simvastatin in rats. J. Gastroenterol. Hepatol. 2007, 22, 2316–2323. [Google Scholar] [CrossRef]
- De Vincenzi, M.; Silano, M.; de Vincenzi, A.; Maialetti, F.; Scazzocchio, B. Safety data review: Constituents of aromatic plants: Eucalyptol. Fitoterapia 2002, 73, 269–275. [Google Scholar] [CrossRef]
- Kirsch, F.; Beauchamp, J.; Buettner, A. Time-dependent aroma changes in breast milk after oral intake of a pharmacological preparation containing 1,8-cineole. J. Clin. Nutr. 2012, 31, 682–692. [Google Scholar] [CrossRef]
- Pattnaick, S.; Subramanyam, V.R.; Bapaji, M.; Kole, C.R. Antibacterial and antifungal activity of aromatic constituents of essential oils. Microbios 1997, 89, 39–46. [Google Scholar]
- Peskar, B.M.; Lange, K.; Hoppe, U.; Peskar, B.A. Ethanol stimulates formation of leukotriene C4 in ratgastric mucosa. Prostaglandins 1986, 31, 283–293. [Google Scholar]
- Alarcon, L.L.C.; Martin, M.J.; Marhuenda, E. Gastric anti-ulcer activity of silymarin, a lipoxygenase inhibitor, in rats. J. Pharm. Pharmacol. 1992, 44, 929–931. [Google Scholar] [CrossRef]
- Boughton-Smith, N.K.; Bhatia, S.P.; McGinty, D.; Letiziam, C.S.; Api, A.M. Involvement of leukotrienes in acute gastric damage. Methods Find. Exp. Clin. Pharmacol. 1989, 11, 53–59. [Google Scholar]
- Juergens, U.R.; Stöber, M.; Vetter, H. Inhibition of cytokine production and arachidonic acid metabolism by eucalyptol (1.8-cineole) in human blood monocytes in vitro. Eur. J. Med. Res. 1998, 3, 508–510. [Google Scholar]
- Santos, F.A.; Silva, R.M.; Campos, A.R.; de Araújo, R.P.; Lima Júnior, R.C.; Rao, V.S. 1,8-cineole (eucalyptol), a monoterpene oxide attenuates the colonic damage in rats on acute TNBS-colitis. Food Chem. Toxicol. 2004, 42, 579–584. [Google Scholar] [CrossRef]
- Kumar, A.; Singh, V.; Chaudhary, A.K. Gastric antisecretory and antiulcer activities of Cedrus deodara (Roxb.) Loud. in Wistar rats. J. Ethnopharmacol. 2011, 134, 294–297. [Google Scholar] [CrossRef]
- Houghton, P.J.; Zarka, R.; de las Heras, B.; Hoult, J.R. Fixed oil of Nigella sativa and derived thymoquinone inhibit eicosanoid generation in leukocytes and membrane lipid peroxidation. Planta Med. 1995, 61, 33–36. [Google Scholar] [CrossRef]
- Kruk, I.; Michalska, T.; Lichszteld, K.; Køadna, A.; Aboul-Enein, H.Y. The effect of thymol and its derivatives on reactions generating reactive oxygen species. Chemosphere 2000, 41, 1059–1064. [Google Scholar] [CrossRef]
- El-Abhar, H.S.; Abdallah, D.M.; Saleh, S. Gastroprotective activity of Nigella sativa oil and its constituent, thymoquinone, against gastric mucosal injury induced by ischaemia/reperfusion in rats. J. Ethnopharmacol. 2003, 84, 251–258. [Google Scholar] [CrossRef]
- Yoshikawa, T.; Naito, Y.; Ueda, S.; Ichikawa, H.; Takahashi, S.; Yasuda, M.; Kondo, M. Ischemia–reperfusion injury and free radical involvement in gastric mucosal disorders. Adv. Exp. Med. Biol. 1992, 316, 231–238. [Google Scholar] [CrossRef]
- Arslan, S.O.; Gelir, T.E.; Armutcu, F.; Coskun, O.; Gurel, A.; Sayan, H.; Celik, I.L. The protective effect of thymoquinone on ethanol-induced acute gastric damage in the rat. Nutr. Res. 2005, 25, 673–680. [Google Scholar] [CrossRef]
- Kanter, M.; Demir, H.; Karakaya, C.; Ozbek, H. Gastroprotective activity of Nigella sativa L oil and its constituent, thymoquinone against acute alcohol-induced gastric mucosal injury in rats. World J. Gastroenterol. 2005, 11, 6662–6666. [Google Scholar]
- Ohta, Y.; Kobayashi, T.; Ishiguro, I. Participation of xanthine– xanthine oxidase system and neutrophils in development of acute gastric mucosal lesions in rats with a single treatment of compound 48/80, a mast cell degranulator. Dig. Dis. Sci. 1999, 44, 1865–1874. [Google Scholar] [CrossRef]
- Ohta, Y.; Kobayashi, T.; Imai, Y.; Inui, K.; Yoshino, J.; Nakazawa, S. Effect of oral Vitamin E administration on acute gastric mucosal lesion progression in rats treated with compound 48/80, a mast cell degranulator. Biol. Pharm. Bull. 2006, 29, 675–683. [Google Scholar] [CrossRef]
- Singh, S.; Khajuria, A.; Taneja, S.C.; Khajuria, R.K.; Singh, J.; Johri, R.K.; Qazi, G.N. The gastric ulcer protective effect of boswellic acids, a leukotriene inhibitor from Boswellia serrata, in rats. Phytomedicine 2008, 15, 408–415. [Google Scholar] [CrossRef]
- Kanter, M.; Coskun, O.; Uysal, H. The antioxidative and antihistaminic effect of Nigella sativa and its major constituent, thymoquinone on ethanol-induced gastric mucosal damage. Arch. Toxicol. 2006, 80, 217–224. [Google Scholar] [CrossRef]
- Chakravarty, N. Inhibition of histamine release from mast cells by nigellone. Ann. Allergy 1993, 70, 237–242. [Google Scholar]
- Magdy, M.A.; Hanan, E.A.; Nabila, E.M. Thymoquinone: Novel gastroprotective mechanisms. Eur. J. Pharmacol. 2012, 697, 126–131. [Google Scholar] [CrossRef]
- Mansour, M.A.; Nagi, M.N.; El-Khatib, A.S.; Al-Bekairi, A.M. Effects of thymoquinone on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase in different tissues of mice: A possible mechanism of action. Cell. Biochem. Funct. 2002, 20, 143–151. [Google Scholar] [CrossRef]
- Al-Ali, A.; Alkhawajah, A.A.; Randhawa, M.A.; Shaikh, N.A. Oral and intraperitoneal LD50 of thymoquinone, an active principle of Nigella sativa, in mice and rats. J. Ayub Med. Coll. Abbottabad 2008, 20, 25–27. [Google Scholar]
- Kacem, R.; Meraihi, Z. Effects of essential oil extracted from Nigella sativa (L.) seeds and its main components on human neutrophil elastase activity. Yakugaku Zasshi 2006, 126, 301–305. [Google Scholar] [CrossRef]
- De Vicenzi, M.; Stammati, A.; de Vicenzi, A.; Silano, M. Constituents of aromatic plants: Carvacrol. Fitoterapia 2004, 75, 801–804. [Google Scholar]
- Jenner, P.M.; Hagan, E.C.; Taylor, J.M.; Cook, E.L.; Fitzhugh, O.G. Food flavourings and compounds of related structure I. Acute oral toxicity. Food Cosmet. Toxicol. 1964, 2, 327–343. [Google Scholar] [CrossRef]
- Fenaroli, G. Fenaroli’s Handbook of Flavor Ingredients, 4th ed.; CRC: Boca Raton, FL, USA, 2001. [Google Scholar]
- Landa, P.; Kokoska, L.; Pribylova, M.; Vanek, T.; Marsik, P. In vitro anti-inflammatory activity of carvacrol: Inhibitory effect on COX-2 catalyzed prostaglandin E(2) biosynthesis. Arch. Pharmacal. Res. 2009, 32, 75–78. [Google Scholar] [CrossRef]
- Guimarães, A.G.; Oliveira, G.F.; Melo, M.S.; Cavalcanti, S.C.; Antoniolli, A.R.; Bonjardim, L.R.; Silva, F.A.; Santos, J.P.; Rocha, R.F.; Moreira, J.C.; et al. Bioassay-guided evaluation of antioxidant and antinociceptive activities of carvacrol. Basic Clin. Pharmacol. Toxicol. 2010, 107, 949–957. [Google Scholar] [CrossRef]
- Silva, F.V.; Guimaraes, A.G.; Silva, E.R.S.; Sousa-Neto, B.P.; Machado, F.D.F.; Quintans-Junior, L.J.; Arcanjo, D.D.R.; Oliveira, F.A.; Oliveira, R.C.M. Anti-inflammatory and anti-ulcer activities of carvacrol, a monoterpene present in the essential oil of Oregano. J. Med. Food 2012, 15, 984–991. [Google Scholar] [CrossRef]
- Okabe, S.; Amagase, S. An overview of acetic acid ulcer models: The history and state of the art of peptic ulcer research. Biol. Pharm. Bull. 2005, 28, 1321–1341. [Google Scholar] [CrossRef]
- Kobayashi, T.; Ohta, Y.; Yoshino, J.; Nakazawa, S. Teprenone promotes the healing of acetic acid-induced chronic gastric ulcers in rats by inhibiting neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues. Pharmacol. Res. 2001, 43, 23–30. [Google Scholar] [CrossRef]
- Shahin, M.; Konturek, P.W.; Pohle, T.; Schuppan, D.; Herbst, H.; Domschke, W. Remodeling of extracellular matrix in gastric ulceration. Microsc. Res. Tech. 2001, 5, 396–408. [Google Scholar]
- Oliveira, I.S.; Silva, F.V.; Viana, A.F.S.C.; Santos, M.R.V.; Quintans-Júnior, L.J.; Martins, M.C.C.; Nunes, P.H.M.; Oliveira, F.A.; Oliveira, R.C.M. Gastroprotective activity of carvacrol on experimentally induced gastric lesions in rodents. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2012, 385, 899–908. [Google Scholar] [CrossRef]
- Hotta, M.; Nakata, R.; Katsukawa, M.; Hori, K.; Takahashi, S.; Inoue, H. Carvacrol, a component of thyme oil, activates PPARalpha and gamma and suppresses COX-2 expression. J. Lipid Res. 2010, 51, 132–139. [Google Scholar] [CrossRef]
- Raina, V.K.; Kumar, A.; Srivastava, S.K.; Syamsundar, K.V.; Kahol, A.P. Essential oil composition of “kewda” (Pandanus odoratissimus) from India. Flavour. Frag. J. 2004, 19, 434–436. [Google Scholar] [CrossRef]
- Harrathi, J.; Hosni, K.; Karray-Bouraoui, N.; Attia, H.; Marzouk, B.; Magné, C.; Lachaâl, M. Effect of salt stress on growth, fatty acids and essential oils in safflower (Carthamus tinctorius L.). Naunyn-Schmiedeberg’s Arch. Pharmacol. 2012, 34, 129–137. [Google Scholar]
- Choi, Y.J.; Sim, C.; Choi, H.K.; Lee, S.H.; Lee, B.H. α-Terpineol induces fatty liver in mice mediated by the AMP-activated kinase and sterol response element binding protein pathway. Food Chem. Toxicol. 2013, 55, 129–136. [Google Scholar] [CrossRef]
- De Sousa, D.P.; Quintans, J.L.; Almeida, R.N. Evaluation of the Anticonvulsant Activity of alfa-Terpineol. Pharm. Biol. 2007, 45, 69–70. [Google Scholar] [CrossRef]
- Quintans-Júnior, L.J.; Oliveira, M.G.B.; Santana, M.F.; Santgana, M.T.; Guimarães, A.G.; Siqueira, J.S.; de Sousa, D.P.; Almeida, R.N. α-terpineol reduces nociceptive behavior in mice. Pharm. Biol. 2011, 49, 583–586. [Google Scholar] [CrossRef]
- Ribeiro, T.P.; Porto, D.L.; Menezes, C.P.; Antunes, A.A.; Silva, D.F.; de Sousa, D.P.; Nakao, L.S.; Braga, V.A.; Medeiros, I.A. Unravelling the cardiovascular effects induced by alpha-terpineol: A role for the nitric oxide-cGMP pathway. Clin. Exp. Pharmacol. Physiol. 2010, 37, 811–816. [Google Scholar]
- Souza, R.H.L.; Cardoso, M.S.P.; Menezes, C.T.; Silva, J.P.; de Sousa, D.P.; Batista, J.S. Gastroprotective activity of α-terpineol in two experimental models of gastric ulcer in rats. Daru 2011, 19, 277–281. [Google Scholar]
- Paisooksantivatana, S.; Bua-in, Y. Essential oil and antioxidant activity of Cassumunar Ginger (Zingiberaceae: Zingiber montanum (Koenig) Link ex Dietr.) collected from various parts of Thailand. Kasetsart J. Nat. Sci. 2009, 43, 467–475. [Google Scholar]
- Sukatta, U.; Rugthaworn, P.; Punjee, P.; Chidchenchey, S.; Keeratinijakal, V. Chemical composition and physical properties of oil from Plai (Zingibercassumunar Roxb.) obtained by hydro distillation and hexane extraction. Kasetsart J. Nat. Sci. 2009, 43, 212–217. [Google Scholar]
- Pazyar, N.; Yaghoobi, R.; Bagheran, N.; Kazerouni, A. A review of applications of tea tree oil in dermatology. Int. J. Dermatol. 2013, 52, 784–790. [Google Scholar] [CrossRef]
- Hamrouni, S.I.; Maamouri, E.; Chahed, T.; Aidi, W.W.; Kchouk, M.E.; Marzouk, B. Effect of growth stage on the content and composition of the essential oil and phenolic fraction of sweet marjoram (Origanum majorana L.). Ind. Crop. Prod. 2009, 30, 395–402. [Google Scholar] [CrossRef]
- Australian Government. Australian Pesticides and Veterinary Medicines Authority. Available online: http://www.apvma.gov.au/advice_summaries/45928.rtf (accessed on 29 April 2014).
- Ninomiya, K.; Hayama, K.; Ishijima, S.A.; Maruyama, N.; Irie, H.; Kurihara, J.; Abe, S. Suppression of inflammatory reactions by terpinen-4-ol, a main constituent of tea tree oil, in a murine model of oral candidiasis and its suppressive activity to cytokine production of macrophages in vitro. Biol. Pharm. Bull. 2013, 36, 838–844. [Google Scholar] [CrossRef]
- Lahlou, S.; Galindo, C.A.B.; Leal-Cardoso, J.H.; Fonteles, M.C.; Duarte, G.P. Cardiovascular effects of the essential oil of Alpinia zerumbet leaves and its main constituent, terpinen-4-ol, in rats: Role of the autonomic nervous system. Planta Med. 2002, 68, 1097–1102. [Google Scholar] [CrossRef]
- Matsunaga, T.; Hasegawa, C.; Kawasuji, T.; Suzuki, H.; Saito, H.; Sagioka, T.; Takahashi, R.; Tsukamoto, H.; Morikawa, T.; Akiyama, T. Isolation of the antiulcer compound in essential oil from the leaves of Cryptomeria japonica. Biol. Pharm. Bull. 2000, 23, 595–598. [Google Scholar] [CrossRef]
- Iacobellis, N.S.; Lo Cantore, P.; Capasso, F.; Senatore, F. Antibacterial activity of Cuminum cyminum L. and Carum carvi L. essential oils. J. Agric. Food Chem. 2005, 53, 57–61. [Google Scholar] [CrossRef]
- Jirovetz, L.; Buchbauer, G.; Shafi, P.M.; Abraham, G.T. Analysis of the essential oil of the roots of the medicinal plant Kaempferia galanga L. (Zingiberaceae) from South India. Acta Pharm. Turc. 2001, 43, 107–110. [Google Scholar]
- Sousa, D.P.; Nóbrega, F.F.F.; Claudino, F.S.; Almeida, R.N.; Leite, J.R.; Mattei, R. Pharmacological effects of the monoterpene α,β-epoxy-carvone in mice. Braz. J. Pharmacogn. 2007, 17, 170–175. [Google Scholar]
- Almeida, R.N.; Sousa, D.P.; Nóbrega, F.F.F.; Claudino, F.S.; Araújo, D.A.M.; Leite, J.R.; Mattei, R. Anticonvulsant effect of a natural compound α,β-epoxy-carvone and its action on the nerve excitability. Neurosci. Lett. 2008, 443, 51–55. [Google Scholar] [CrossRef]
- Arruda, T.A.; Antunes, R.M.P.; Catão, R.M.R.; Lima, E.O.; Sousa, D.P.; Nunes, X.P.; Pereira, M.S.V.; Barbosa-Filho, J.M.; da Cunha, E.V.L. Preliminary study of the antimicrobial activity of Mentha. x villosa Hudson essential oil, rotundifolone and its analogues. Rev. Bras. Farmacogn. 2006, 16, 307–311. [Google Scholar] [CrossRef]
- Rocha, M.L.; Oliveira, L.E.G.; Santos, C.M.P.; Sousa, D.P.; Almeida, R.N.; Araujo, D.A.M. Antinociceptive and anti-inflammatory effects of the monoterpene α-β-epoxy-carvone in mice. J. Nat. Med. 2013, 67, 743–749. [Google Scholar] [CrossRef]
- Siqueira, B.P.J.; Menezes, C.T.; Silva, J.P.; Sousa, D.P.; Batista, J.S. Antiulcer effect of epoxy-carvone. Braz. J. Pharmacogn 2012, 22, 144–149. [Google Scholar]
- Belsito, D.; Bickers, D.; Bruze, M.; Calow, P.; Greim, H.; Hanifin, J.M.; Rogers, A.E.; Saurat, J.H.; Sipes, I.G.; Tagami, H. A toxicologic and dermatologic assessment of cyclic and non-cyclic terpene alcohols when used as fragrance ingredientes (Review). Food Chem. Toxicol. 2008, 46, 1–71. [Google Scholar] [CrossRef]
- Bhatia, S.P.; Letizia, S.C.; Api, A.M. Fragrance material review on elemol. Food Chem. Toxicol. 2008, 46, 147–148. [Google Scholar] [CrossRef]
- Paluch, G.; Grodnitzky, J.; Bartholomay, L.; Coats, J. Quantitative structure–activity relationship of botanical sesquiterpenes: Spatial and contact repellency to the yellow fever mosquito, Aedes aegypti. J. Agric. Food Chem. 2009, 57, 7618–7625. [Google Scholar] [CrossRef]
- Wedge, D.E.; Tabanca, N.; Sampson, B.J.; Werle, C.; Demirci, B.; Baser, K.H.; Nan, P.; Duan, J.; Liu, Z. Antifungal and insecticidal activity of two Juniperus essential oils. Nat. Prod. Commun. 2009, 4, 123–127. [Google Scholar]
- Vila, R.; Mundina, M.; Muschietti, L.; Priestap, H.A.; Bandoni, A.L.; Adzet, T.; Canigueral, S. Volatile constituents of leaves, roots and stems from Aristolochia elegans. Phytochemistry 1997, 46, 1127–1129. [Google Scholar] [CrossRef]
- Péres, V.F.; Moura, D.J.; Sperotto, A.R.; Damasceno, F.C.; Caramão, E.B.; Zini, C.A.; Saffi, J. Chemical composition and cytotoxic, mutagenic and genotoxic activities of the essential oil from Piper gaudichaudianum Kunth leaves. Food Chem. Toxicol. 2009, 47, 2389–2395. [Google Scholar] [CrossRef]
- Klopell, F.C.; Lemos, M.; Sousa, J.P.; Comunello, E.; Maistro, E.L.; Bastos, J.K.; de Andrade, S.F. Nerolidol, an antiulcer constituent from the essential oil of Baccharis dracunculifolia DC (Asteraceae). Z. Naturforsch. C 2007, 62, 537–542. [Google Scholar]
- Massignani, J.J.; Lemos, M.; Maistro, E.L.; Schaphauser, H.P.; Jorge, R.F.; Sousa, J.P.B.; Bastos, J.K.; Andrade, S.F. Antiulcerogenic Activity of the Essential Oil of Baccharis dracunculifolia on Different Experimental Models in Rats. Phytother. Res. 2009, 23, 1355–1360. [Google Scholar] [CrossRef]
- Kim, S.; Jung, E.; Kim, J.H.; Park, Y.O.; Lee, J.; Park, D. Inhibitory effects of (−)-α-bisabolol on LPS-induced inflammatory response in RAW264.7 macrophages. Food Chem. Toxicol. 2011, 49, 2580–2585. [Google Scholar] [CrossRef]
- Andersen, F.A. Final report on the safety assessment of Bisabolol. Int. J. Toxicol. 1999, 18, 33–44. [Google Scholar] [CrossRef]
- Avonto, C.; Wang, M.; Chittiboyina, A.G.; Avula, B.; Zhao, J.; Khan, I.A. Hydroxylated bisabolol oxides: Evidence for secondary oxidative metabolism in Matricaria chamomilla. J. Nat. Prod. 2013, 76, 1848–1853. [Google Scholar] [CrossRef]
- Vila, R.; Santana, A.I.; Perez-Roses, R.; Valderrama, A.; Castelli, M.V.; Mendonca, S.; Zacchino, S.; Gupta, M.P.; Canigueral, S. Composition and biological activity of the essential oil from leaves of Plinia cerrocampanensis, a new source of alpha-bisabolol. Bioresour. Technol. 2010, 101, 2510–2514. [Google Scholar] [CrossRef]
- Leite, G.O.; Leite, L.H.I.; Sampaio, R.S.; Araruna, M.K.A.; Menezes, I.R.A.; Costa, J.G.M.; Campos, A.R. (−)-α-Bisabolol attenuates visceral nociception and inflammation in mice. Fitoterapia 2011, 82, 208–211. [Google Scholar] [CrossRef]
- Silva, A.P.; Martini, M.V.; Oliveira, C.M.; Cunha, S.; Carvalho, J.E.; Ruiz, A.L.; Silva, C.C. Antitumor activity of (−)-alpha-bisabolol-based thiosemicarbazones against human tumor cell lines. Eur. J. Med. Chem. 2010, 45, 2987–2993. [Google Scholar] [CrossRef]
- Bezerra, S.B.; Leal, L.K.A.M.; Nogueira, N.A.P.; Campos, A.R. Bisabolol-induced gastroprotection against acute gastric lesions: Role of prostaglandins, nitric oxide, and KATP+ Channels. J. Med. Food 2009, 12, 1403–1406. [Google Scholar] [CrossRef]
- Rocha, N.F.M.; Venancio, E.T.; Moura, B.A.; Silva, M.I.G.; Aquino Neto, M.F.; Rios, V.E.R.; Sousa, D.P.; Vasconcelos, S.M.M.; Fonteles, M.M.F.; Sousa, F.C.F. Gastroprotection of (−)-α-bisabolol on acute gastric mucosal lesions in mice: The possible involved pharmacological mechanisms. Fundam. Clin. Pharmacol. 2010, 24, 63–71. [Google Scholar] [CrossRef]
- Halici, M.; Odabasoglu, F.; Suleyman, H.; Cakir, A.; Aslan, A.; Bayir, Y. Effects of water extract of Usnea longissima on antioxidant enzyme activity and mucosal damage caused by indomethacin in rats. Phytomedicine 2005, 12, 656–662. [Google Scholar] [CrossRef]
- Rocha, N.F.M.; Rios, E.R.V.; Carvalho, A.M.R.; Cerqueira, G.S.; Lopes, A.A.; Leal, L.K.A.M.; Dias, M.L.; Sousa, D.P.; Sousa, C.F.C. Anti-nociceptive and anti-inflammatory activities of (−)-α-bisabolol in rodents. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2011, 384, 525–533. [Google Scholar] [CrossRef]
- Dursun, H.; Bilici, M.; Albayrak, F.; Ozturk, C.; Saglam, M.B.; Alp, H.H.; Suleyman, H. Antiulcer activity of fluvoxamine in rats and its effect on oxidant and antioxidant parameters in stomach tissue. BMC Gastroenterol. 2009, 9, 36. [Google Scholar] [CrossRef]
- Sannomiya, M.; Fonseca, V.B.; da Silva, M.A.; Rocha, L.R.; Dos Santos, L.C.; Hiruma-Lima, C.A.; Souza Brito, A.R.; Vilegas, W. Flavonoids and antiulcerogenic activity from Byrsonima crassa leaves extracts. J. Ethnopharmacol. 2005, 97, 1–6. [Google Scholar] [CrossRef]
- Mates, J.M.; Perez-Gomez, C.; Castro, I.N. Antioxidant enzymes and human diseases. Clin. Biochem. 1999, 32, 595–603. [Google Scholar] [CrossRef]
- Yoshikawa, T.; Minamiyama, Y.; Ichikawa, H.; Takahashi, S.; Naito, Y.; Kondo, M. Role of lipid peroxidation and antioxidants in gastric mucosal injury induced by the hypoxanthine-x anthine oxidase system in rats. Free Radic. Bio. Med. 1997, 23, 243–250. [Google Scholar] [CrossRef]
- Huang, X.R.; Chun Hui, C.W.; Chen, Y.X. Macrophage migration inhibitory factor is an important mediator in the pathogenesis of gastric inflammation in rats. Gastroenterology 2001, 121, 619–630. [Google Scholar] [CrossRef]
- Chainy, G.B.; Manna, S.K.; Chaturvedi, M.M.; Aggarwal, B.B. Anethole blocks both early and late cellular responses transduced by tumor necrosis factor: Effect on NF-kappaB, AP-1, JNK, MAPKK and apoptosis. Oncogene 2000, 19, 2943–2950. [Google Scholar] [CrossRef]
- Ghelardini, C.; Galeotti, N.; Mazzanti, G. Local anaesthetic activity of monoterpenes and phenylpropanes of essential oils. Planta Med. 2001, 67, 564–566. [Google Scholar] [CrossRef]
- Freire, R.S.; Morais, S.M.; Catunda-Junior, F.E.A.; Pinheiro, D.C.S.N. Synthesis and antioxidant, anti-inflammatory and gastroprotector activities of anethole and related compounds. Bioorg. Med. Chem. 2005, 13, 4353–4358. [Google Scholar] [CrossRef]
- Miller, H.E. A simplified method for the evaluation of antioxidant. J. Am. Oil Chem. Soc. 1971, 48, 91. [Google Scholar] [CrossRef]
- Craveiro, A.A.; Andrade, C.H.; Matos, F.J.; Alencar, J.W.; Dantas, T.N. Fixed and volatile constituents of Croton aff. nepetifolius. J. Nat. Prod. 1980, 43, 756–757. [Google Scholar] [CrossRef]
- Coelho-de-Souza, A.N.; Criddle, D.N.; Leal-Cardoso, J.H. Selective and modulatory effects of the essential oil of Croton zehntneri on isolated smooth muscle preparations of the guinea pig. Phytother. Res. 1998, 12, 189–194. [Google Scholar] [CrossRef]
- Coelho-De-Souza, A.N.; Lahlou, S.; Barreto, J.E.F.; Yum, M.E.M.; Oliveira, A.C.; Oliveira, H.D.; Celedonio, N.R.; Feitosa, R.G.R.; Duarte, G.P.; Santos, C.F.; et al. Essential oil of Croton zehntneri and its major constituent anethole display gastroprotective effect by increasing the surface mucous layer. Fundam. Clin. Pharmacol. 2013, 27, 288–298. [Google Scholar] [CrossRef]
- Hagan, E.C.; Jenner, P.M.; Jones, W.I.; Fitzhugh, O.G.; Long, E.L.; Brouwer, J.G.; Dwebb, W.K. Toxic properties of compounds related to safrole. Toxic. Appl. Pharmac. 1965, 7, 18–24. [Google Scholar] [CrossRef]
- Taylor, J.M.; Jenner, P.M.; Jones, W.I. A comparison of the toxicity of some allyl, propenyl and propyl compounds in the rat. Toxic. Appl. Pharm. 1964, 2, 378. [Google Scholar] [CrossRef]
- Truhaut, R.; Le Bourhis, B.; Attia, M.; Glomot, R.; Newman, J.; Caldwell, J. Chronic toxicity/carcinogenicity study of trans-anethole in rats. Food Chem. Toxicol. 1989, 27, 11–20. [Google Scholar] [CrossRef]
- Cai, L.; Wu, C.D. Compounds from Syzygium aromaticum possessing growth inhibitory activity against oral pathogens. J. Nat. Prod. 1996, 59, 987–990. [Google Scholar] [CrossRef]
- Sober, H.A.; Hollander, F.; Sober, E.K. Toxicity of eugenol determination of LD50 on rats. Exp. Biol. Med. 1950, 73, 148–151. [Google Scholar] [CrossRef]
- Sax, N.I. Dangerous Properties of Industrial Materials, 11th ed.; Lewis, R.J., Sr., Ed.; Wiley-Interscience. Wiley & Sons, Inc.: Hoboken, NJ, USA, 2004; p. 1735. [Google Scholar] [CrossRef]
- Kim, H.M.; Lee, E.H.; Kim, C.Y.; Chung, J.G.; Kim, S.H.; Lim, J.P.; Shin, T.Y. Antianaphylactic properties of eugenol. Pharmacol. Res. 1997, 36, 475–680. [Google Scholar] [CrossRef]
- Sharma, J.N.; Srivastava, K.C.; Gan, E.K. Suppressive effects of eugenol and ginger oil on arthritic rats. Pharmacology 1994, 49, 314–318. [Google Scholar] [CrossRef]
- Santin, J.R.; Lemos, M.; Klein-Júnior, L.C.; Machado, I.D.; Costa, P.; Oliveira, A.P.; Tilia, C.; Souza, J.P.; Sousa, J.P.B.; Bastos, J.K.; et al. Gastroprotective activity of essential oil of the Syzygium aromaticum and its major component eugenol in different animal models. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2011, 383, 149–158. [Google Scholar] [CrossRef]
- Hiruma-Lima, C.A.; Santos, L.C.; Kushima, H.; Pellizzon, C.H.; Silveira, G.G.; Vasconcelos, P.C.P.; Vilegas, W.; Souza Brito, A.R.M. Qualea grandiflora, a Brazilian “Cerrado” medicinal plant presents an important antiulcer activity. J. Ethnopharmacol. 2006, 104, 207–214. [Google Scholar] [CrossRef]
- Capasso, R.; Pinto, L.; Vuotto, M.L.; di Carlo, G. Preventive effect of eugenol on PAF and ethanol-induced gastric mucosal damage. Fitoterapia 2000, 71, 131–137. [Google Scholar] [CrossRef]
- Maity, P.; Biswas, K.; Roy, S.; Banerjee, R.K.; Bandyopadhyay, U. Smoking and the pathogenesis of gastroduodenal ulcer—recent mechanistic update. Mol. Cel. Biochem. 2003, 253, 329–338. [Google Scholar] [CrossRef]
- Braquet, P.; Etienne, A.; Mencia-Huerta, J.M.; Clostre, F. Effects of the specific platelet-activating factor antagonists, BN 52021 and BN 52063, on various experimental gastrointestinal ulcerations. Eur. J. Pharmacol. 1988, 150, 269–276. [Google Scholar] [CrossRef]
- Morsy, M.A.; Fouad, A.A. Mechanisms of gastroprotective effect of eugenol in indomethacin-induced ulcer in rats. Phytother. Res. 2008, 22, 1361–1366. [Google Scholar] [CrossRef]
- Souza, M.H.L.P.; Lemos, H.P.; Oliveira, R.B.; Cunha, F.Q. Gastric damage and granulocyte infiltration induced by indomethacin in tumour necrosis factor receptor 1 (TNF-R1) or inducible nitric oxide synthase (iNOS) deficient mice. Gut 2004, 53, 791–796. [Google Scholar] [CrossRef]
- Yoshikawa, T.; Naito, Y.; Kishi, A.; Tomii, T.; Kaneko, T.; Iinuma, S.; Ichikawa, H.; Yasuda, M.; Takahashi, S.; Kondo, M. Role of active oxygen, lipid peroxidation, and antioxidants in the pathogenesis of gastric mucosal injury induced by indomethacin in rats. Gut 1993, 34, 732–737. [Google Scholar] [CrossRef]
- Goel, R.K.; Bhattacharya, S.K. Gastroduodenal mucosal defense and protective agents Indian. J. Exp. Biol. 1991, 29, 701–714. [Google Scholar]
- Iwai, T.; Ichikawa, T.; Goso, Y.; Ikezawa, T.; Saegusa, Y.; Okayasu, Y.; Saigenji, K.; Ishihara, K. Effects of indomethacin on the rat small intestinal mucosa: Immunohistochemical and biochemical studies using anti-mucin monoclonal antibodies. J. Gastroenterol. 2009, 44, 277–284. [Google Scholar] [CrossRef]
- Jung, J.; Lee, J.H.; Bae, K.H.; Jeong, C.S. Anti-gastric actions of eugenol and cinnamic acid isolated from Cinnamoni ramulus. Yakugaku Zasshi 2011, 131, 1103–1110. [Google Scholar] [CrossRef]
- Marhuenda, E.; Martin, M.J.; Alarcon De La Lastra, C. Antiulcerogenic activity of aescine in different experimental models. Phytother. Res. 1993, 7, 13–16. [Google Scholar] [CrossRef]
- Yamahara, J.; Mochizuki, M.; Rong, H.Q.; Matsuda, H.; Fujimura, H. The anti-ulcer effect in rats of ginger constituents. J. Ethnopharmacol. 1988, 23, 299–304. [Google Scholar] [CrossRef]
- Yang, X.; Eilerman, R.G. Pungent Principal of Alpinia. galangal (L.) Swartz and Its Applications. J. Agric. Food Chem. 1999, 47, 1657–1662. [Google Scholar] [CrossRef]
- Nakamura, Y.; Murakami, A.; Ohto, Y.; Torikai, K.; Tanaka, T.; Ohigashi, H. Suppression of tumor promoter-induced oxidative stress and inflammatory responses in mouse skin by a superoxide generation inhibitor 1V-acetoxychavicol acetate. Cancer Res. 1998, 58, 4832–4839. [Google Scholar]
- Kubota, K.; Ueda, Y.; Yasuda, M.; Masuda, A. Occurrence and antioxidative activity of 1V-acetoxychavicol acetate and its related compounds in the rhizomes of Alpinia galanga during cooking. Spec. Publ. R. Soc. Chem. 2001, 274, 601–607. [Google Scholar]
- Mitsui, S.; Kobayashi, S.; Nagahori, H.; Ogiso, A. Constituents from seeds of Alpinia galanga WILD and their anti-ulcer activies. Chem. Pharm. Bull. 1976, 24, 2377–2382. [Google Scholar] [CrossRef]
- Matsuda, H.; Pongpiriyadacha, Y.; Morikawa, T.; Ochi, M.; Yoshikawa, M. Gastroprotective effects of phenylpropanoids from the rhizomes of Alpinia galanga in rats: Structural requirements and mode of action. Eur. J. Pharmacol. 2003, 471, 59–67. [Google Scholar] [CrossRef]
- Gruenwald, J.; Freder, J.; Armbruester, N. Cinnamon and health. Crit. Rev. Food Sci. Nutr. 2012, 50, 822–834. [Google Scholar]
- Leach, M.J.; Kumar, S. Cinnamon for diabetes mellitus. Cochrane Database Syst. Rev. 2012, 9. [Google Scholar] [CrossRef]
- Keshvari, M.; Asgary, S.; Jafarian-Dehkordi, A.; Najafi, S.; Ghoreyshi-Yazdi, S.M. Preventive effect of cinnamon essential oil on lipid oxidation of vegetable oil. Atherosclerosis 2013, 9, 280–286. [Google Scholar]
- Mereto, E.; Brambilla-Campart, G.; Ghia, M.; Martelli, A.; Brambilla, G. Cinnamaldehyde-induced micronuclei in rodent liver. Mutat. Res. 1994, 322, 1–8. [Google Scholar] [CrossRef]
- Shreaz, S.; Bhatia, R.; Khan, N.; Muralidhar, S.; Basir, S.F.; Manzoor, N.; Khan, L.A. Spice oil cinnamaldehyde exhibits potent anticandidal activity against fluconazole resistant clinical isolates. Fitoterapia 2010, 82, 1012–1020. [Google Scholar]
- Liao, J.C.; Deng, J.S.; Chiu, C.S.; Hou, W.C.; Huang, S.S.; Shie, P.H.; Huang, G.J. Anti-inflammatory activities of Cinnamomum cassia constituents in vitro and in vivo. Evid. Based Complement. Altern. Med. 2012, 429320. 1–12. [Google Scholar]
- Kim, B.H.; Lee, Y.G.; Lee, J.; Lee, J.Y.; Cho, J.Y. Regulatory effect of cinnamaldehyde on monocyte/macrophage-mediated inflammatory responses. Mediat. Inflamm. 2010, 2010, 1–9. [Google Scholar]
- Wondrak, G.T.; Villeneuve, N.F.; Lamore, S.D.; Bause, A.S.; Jiang, T.; Zhang, D.D. The cinnamon-derived dietary factor cinnamic aldehyde activates the Nrf2-dependent antioxidant response in human epithelial colon cells. Molecules 2010, 15, 3338–3355. [Google Scholar] [CrossRef]
- El-Bassossy, H.M.; Fahmy, A.; Badawy, D. Cinnamaldehyde protects from the hypertension associated with diabetes. Food Chem. Toxicol. 2011, 49, 3007–3012. [Google Scholar] [CrossRef]
- Tankam, J.M.; Sawada, Y.; Ito, M. Regular ingestion of Cinnamomi cortex pulveratus offers gastroprotective activity in mice. J. Nat. Med. 2013, 67, 289–295. [Google Scholar] [CrossRef]
- Harada, M.; Yano, S. Pharmacological studies on Chinese cinnamon. Effects of cinnamaldehyde on the cardiovascular and digestive systems. Chem. Pharm. Bull. 1975, 23, 941–947. [Google Scholar] [CrossRef]
- Ali, S.M.; Khan, A.A.; Ahmed, I.; Musaddiq, M.; Ahmed, K.S.; Polasa, H.; Rao, L.V.; Habibullah, C.M.; Sechi, L.A.; Ahmed, N. Antimicrobial activities of Eugenol and Cinnamaldehyde against the human gastric pathogen Helicobacter pylori. Ann. Clin. Microbiol. Antimicrob. 2005, 4, 20. [Google Scholar] [CrossRef]
- Levenstein, I. Acute Oral Toxicity Study in Rats and Acute Dermal Toxicity Study in Rabbits; Unpublished Report to Research Institute for Fragrance Materials Inc.: Englewood Cliffs, NJ, USA, 1976. [Google Scholar]
- Zaitsev, A.N.; Rakhmanina, N.L. Toxic properties of pheny-lethanol and cinnamic alcohol derivatives. Vopr. Pitan. 1974, 5, 48–53. [Google Scholar]
- Conti, B.R.; Búfalo, M.C.; Golim, M.A.; Bankova, V.; Sforcin, J.M. Cinnamic acid is partially involved in propolis immunomodulatory action on human monocytes. Evid. Based Complement. Alternat. Med. 2013, 2013, 1–7. [Google Scholar]
- Villena, J.; Kitazawa, H. Modulation of intestinal TLR4-inflammatory signaling pathways by probiotic microorganisms: Lessons learned from Lactobacillus jensenii TL2937. Front. Immunol. 2014, 4, 512. [Google Scholar]
- Adisakwattana, S.; Sompong, W.; Meeprom, A.; Ngamukote, S.; Yibchok-Anun, S. Cinnamic acid and its derivatives inhibit fructose-mediated protein glycation. Int. J. Mol. Sci. 2012, 13, 1778–1789. [Google Scholar] [CrossRef]
- Furia, T.E.; Bellanca, N. Fenaroli’s Handbook of Flavor Ingredients; Chemical Rubber Company Press: Cleveland, OH, USA, 1975; p. 2. [Google Scholar]
- Ress, N.B.; Hailey, J.R.; Maronpot, R.R.; Bucher, J.R.; Travlos, G.S.; Haseman, J.K.; Orzech, D.P.; Johnson, J.D.; Hejtmancik, M.R. Toxicology and carcinogenesis studies of microencapsulated citral in rats and mice. Toxicol. Sci. 2003, 71, 198–206. [Google Scholar] [CrossRef]
- Ortiz, M.I.; Ramírez-Montiel, M.L.; González-García, M.P.; Ponce-Monter, H.A.; Castañeda-Hernández, G.; Cariño-Cortés, R. The combination of naproxen and citral reduces nociception and gastric damage in rats. Arch. Pharm. Res. 2010, 10, 1691–1697. [Google Scholar]
- Derby, R.; Rohal, P.; Jackson, C.; Beutler, A.; Olsen, C. Novel treatment of onychomycosis using over-the-counter mentholated ointment: A clinical case series. J. Am. Board Fam. Med. 2011, 24, 69–74. [Google Scholar] [CrossRef]
- Ait-Ouazzou, A.; Cherrat, L.; Espina, L.; Loran, S.; Rota, C.; Pagan, R. The antimicrobial activity of hydrophobic essential oil constituents acting alone or in combined processes of food preservation. Innov. Food Sci. Emerg. 2011, 12, 320–329. [Google Scholar] [CrossRef]
- Qiu, J.Z.; Wang, D.C.; Xiang, H.; Feng, H.H.; Jiang, Y.S.A.; Xia, L.J. Subinhibitory concentrations of thymol reduce enterotoxins A and B and alpha-hemolysin production in Staphylococcus aureus isolates. PLoS One 2010, 5, e9736. [Google Scholar]
- Dhaneshwar, S.; Patel, V.; Patil, D.; Meena, G. Studies on synthesis, stability, release and pharmacodynamic profile of a novel diacerein-thymol prodrug. Bioorg. Med. Chem. Lett. 2013, 23, 55–61. [Google Scholar] [CrossRef]
- Rintelen, B.; Neumann, K.; Leeb, B.F. A meta-analysis of controlled clinical studies with diacerein in the treatment of osteoarthritis. Arch. Intern. Med. 2006, 166, 1899–1906. [Google Scholar] [CrossRef]
- Rainsford, K.D. Aspirin and gastric ulceration: Light and electron microscopic observations in a model of aspirin plus stress-induced ulcerogenesis. Br. J. Exp. Pathol. 1977, 58, 215–219. [Google Scholar]
- Jung, H.W.; Mahesh, R.; Park, J.H.; Boo, Y.C.; Park, K.M.; Park, Y.K. Bisabolangelone isolated from Ostericum koreanum inhibits the production of inflammatory mediators by down-regulation of NF-kappaB and ERK MAP kinase activity in LPS-stimulated RAW264.7 cells. Int. Immunopharmacol. 2010, 10, 155–162. [Google Scholar] [CrossRef]
- Wang, J.; Zhu, L.; Zou, K.; Cheng, F.; Dan, F.; Guo, Z.; Cai, Z.; Yang, J. The antiulcer activities of bisabolangelone from Angelica polymorpha. J. Ethnopharmacol. 2009, 123, 343–346. [Google Scholar] [CrossRef]
- Kim, H.S.; Lee, Y.J.; Lee, H.K.; Kim, J.S.; Park, Y.; Kang, J.S.; Hwang, B.Y.; Hong, J.T.; Kim, Y.; Han, S.B. Bisabolangelone inhibits dendritic cell functions by blocking MAPK and NF-jB signaling. Food Chem. Toxicol. 2013, 59, 26–33. [Google Scholar] [CrossRef]
- Zhan, Y. The Medicinal Source of China Shennongjia; The Science and Technological Press of Hubei: Hubei, China, 1994; pp. 418–419. [Google Scholar]
- Fang, Z.; Liao, Z. The Medicinal Plants from Enshi of Hubei; The Science and Technological Press of Hubei: Hubei, China, 2006; p. 116. [Google Scholar]
- Hata, K.; Kozawa, M.; Ikeshiro, Y. On the coumarins of the roots of Angelica polymorpha Maxim. (Umbelliferae). Yakugaku Zasshi 1967, 87, 464–465. [Google Scholar]
- Yang, Y.; Zhang, Y.; Ren, F.X.; Yu, N.J.; Xu, R.; Zhao, Y.M. Chemical constituents from the roots of Angelica polymorpha Maxim. Yao Xue Xue Bao. 2013, 48, 718–722. [Google Scholar]
- Cai, Z.J.; Dan, F.J.; Cheng, F.; Wang, J.Z.; Zou, K. Chemical constituents of antibacterial activity fraction of Angelica polymorpha. Zhong Yao Cai 2008, 31, 1160–1162. [Google Scholar]
© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).