Scientific Evaluation of Edible Fruits and Spices Used for the Treatment of Peptic Ulcer in Traditional Iranian Medicine

In traditional Iranian medicine (TIM), several edible fruits and spices are thought to have protective and healing effects on peptic ulcer (PU). The present study was conducted to verify anti-PU activity of these remedies. For this purpose, edible fruits and spices proposed for the management of PU in TIM were collected from TIM sources, and they were searched in modern medical databases to find studies that confirmed their efficacy. Findings from modern investigations support the claims of TIM about the efficacy of many fruits and spices in PU. The fruit of Phyllanthus emblica as a beneficial remedy for PU in TIM has been demonstrated to have antioxidant, wound healing, angiogenic, anti-H. pylori, cytoprotective, antisecretory, and anti-inflammatory properties. The fruit of Vitis vinifera has been found to be anti-H. pylori, anti-inflammatory, wound healing, angiogenic, cytoprotective, and antioxidant. The fruit and aril of seed from Myristica fragrans exert their beneficial effects in PU by increasing prostaglandin, modulation of nitric oxide and inflammatory mediators, wound healing, antisecretory, antacid, antioxidant, and anti-H. pylori activities, and improving angiogenesis. Pharmacological and clinical studies for evaluation of efficacy of all TIM fruits and spices in PU and their possible mechanisms of action are recommended.


Introduction
Gastric and duodenal ulcers, entitled as peptic ulcer (PU), are the most prevalent gastrointestinal disorders in the world [1]. PU is a multifactorial and complex disease with unclear etiological factor. It has been demonstrated that PU is a pathological condition in which biological balance between aggressive and defense factors is disturbed. Among aggressive factors, it can be named from gastric acid and pepsin secretion, active free radicals and oxidants, leukotrienes, endothelins, and exogenous factors such as ethanol or nonsteroidal anti-inflammatory drugs (NSAIDs). In contrast, gastric mucus, bicarbonate, normal blood flow, prostaglandin (PG), nitric oxide (NO), and antioxidant enzymes such as catalase and glutathione (GSH) work as defense factors [2,3].
Most of the gastric lesions originate from a chronic infection of gastric mucosa with Helicobacter pylori (H. pylori). H. pylori is a common human pathogen with asymptomatic stomach colonization in nearly 70% of the population and approximately 10%-20% are susceptible for PU [4].
Traditional medicines of all over the world possess different virgin remedies for the treatment of symptomatologies related to many ailments. Thus, they are very important for investigation on their efficacy and phytochemical constituents [5][6][7]. There are several edible fruits and spices proposed in traditional Iranian medicine (TIM) for the management of PU [8,9]. Present study conducted to review these fruits and spices and found evidence for their efficacy and biological mechanisms in modern publications. In order to achieve this aim, electronic databases including PubMed, 2 ISRN Gastroenterology Scopus, Web of Science, and Google Scholar were explored for each of the medicinal plants recommended in TIM for PU, and all retrieved articles were evaluated to obtain any in vitro, in vivo, or clinical evidence for their efficacy and possible mechanisms. The retrieved studies either explain clearly effectiveness of these herbs or indirectly their efficacy on the involved mechanisms in the treatment of PU.

Edible Fruits and Spices for the Treatment of PU in TIM
Scientific, common English and traditional Iranian names of edible fruits and spices used in TIM for the management of PU with their plant family and pharmacological activities in TIM have been shown in Table 1. Moreover, details of in vitro and in vivo findings that support their efficacy in PU have been demonstrated in Table 2. Below, these fruits and spices with their possible mechanisms of action in PU have been described alphabetically.

Amygdalus communis.
A. communis demonstrated a trivial antacid property in vitro [10], and different parts of fruit showed antioxidant activity [11,12]. Topical application of bitter almond oil healed wounds in rats [13]. Amygdalin, a glycoside isolated from Amygdalus genus, revealed gastroprotective properties through suppression of inflammatory cytokines [14].

Berberis vulgaris L.
Fruit has shown antioxidant activity [15] and may have a role in improvement of intestinal mucosal morphology [18]. Berberine, as an active constituent of fruit, promoted releasing NO in the intestinal endothelium [16]. It showed inhibitory activity on H. pylori growth [17] and gastroprotective effect through modulating NO synthase (NOS) gene expression [19]. It also had protective activity against small intestinal injury and increased adenosine in the intestinal tissue [20]. However, there is a report about dose-dependent gastric ulcer inducing activity of berberine from B. crataegina during acute toxicity test in mice [21].

Cucurbita maxima
Duch. and C. Pepo L. Fruit pulp of C. pepo showed protective activity against gastric and duodenal ulcer via enhancing mucosal thickness and increasing alkaline phosphatase enzyme in stomach and duodenum tissue [25]. Triterpenoids from the seeds of C. pepo protected against gastric ulcer via reducing gastric secretion and free and total acidity of gastric juice and its antioxidant activity [24].
2.6. Malus domestica Baumg. M. domestica fruit and its isolated phenolic acids demonstrated gastroprotective activity via reducing neutrophil infiltration in gastric tissue and antioxidant activity [30,31]. The fruit also reduced gastric endothelial cell injury through antioxidant activity [31]. M. domestica peel showed both in vitro and in vivo anti H. pylori activity [32,33]. Fruit polyphenol revealed gastroprotective activity without significant effect on gastric secretion. It also inhibited lipid peroxidation and production of inflammatory cytokines [34]. However, there is a report on exacerbation of gastric ulcer by fruit polyphenol extract [27].

Morus alba L. and M. nigra L.
Cyanidin-3-O-glucoside, a component isolated from M. alba fruit, showed protective activity against endothelial dysfunction [36]. Ethyl acetate soluble fraction of fruit attenuated gastric ulceration in rat via its antioxidant activity [38]. The leaf had protective activity against gastric ulcer [35] and revealed anti H. pylori as well as antioxidant activity [37].

Myristica fragrans Houtt.
Various investigations have proved strong anti-H. Pylori activity of M. fragrans seed in vitro [39]. Dihydroguaiaretic acid isolated from aril of the seed also demonstrated strong anti H. pylori activity [40]. The seeds suppressed free and total acidity and volume of gastric secretion [42]. The aril of seed showed antioxidant activity in vitro [41]. M. malabarica fruits improved gastric ulcer in mice via increasing PG E2 synthesis, improving angiogenesis, modulating NOS gene expression, producing balance between proinflammatory and anti-inflammatory cytokines, and improving mucin content and antioxidant activity in gastric tissue [44][45][46]. M. andamanica leaves demonstrated wound healing activity in vivo [47]. A polyherbal formulation containing M. fragrans fruits inhibits gastric ulcer and hypersecretion in rats [43].
2.9. Oryza sativa L. O. sativa bran oil protected gastric mucus from stress-induced ulcers in rats via inhibiting acid secretion. O. sativa reduced basal acid secretion and stimulated gastric acid secretion by histamine in rats [50]. Antioxidant activity of normal and pigmented rice brans and some isolated components has been proved in vitro [48]. O. sativa cooked seeds suppressed intestinal secretion through inhibiting the response of intestinal epithelial crypt cells to adenosine 3 ,5 -cyclic monophosphate, a major intracellular mediator of secretion [51]. Rice fluid exhibited strong bactericidal activity against H. pylori [49]. In spite of these supportive data, Jayaraj et al. demonstrated that oil derived from rice and rice bran on storage becomes ulcerogenic, while fresh rice bran diet protected mucosa from ulceration [52].
The study evaluating dietary profile of patients with duodenal ulcer showed more ulcer occurrence in patient with rice diets. Moreover, mucin activity was attenuated, and severity of ulcer induced by pylorus ligation was higher in rice diet rats [53].

Phoenix dactylifera L.
Fruit and seed possess antioxidant activity [54,55]. The fruit ameliorated gastric ulcers via increasing gastric mucin and reducing histamine and gastrin (a gastrointestinal hormone that regulates gastric acid secretion, releases histamine, and regulates gastric endocrine cell proliferation in the plasma) [56].
2.11. Phyllanthus emblica L. P. emblica fruit purified phenolics demonstrated antioxidant activity in vitro [57]. The fruit exhibited wound healing activity via improvement of collagen function and enhancing antioxidant capacity [59]. It protected against gastric ulcer via its antioxidant and cytoprotective activity [60,62]. Gallic acid enriched extract exhibited healing property on gastric ulcer via increasing PG E 2 and proangiogenesis factors, enhancing endothelial NOS (eNOS), and regulation of pro-inflammatory and antiinflammatory cytokines and antioxidant activity [61,63]. The fruit ethanol extract demonstrated anti H. pylori activity in vitro [58].
2.12. Punica granatum L. P. granatum peel extract protected gastric mucus from gastric ulcer via its antioxidant activity and attenuating gastric acidity [67,68]. It attenuated acetylcholine-induced contractions and inhibition of the spontaneous movement of the isolated rat ileum [64]. The peel also showed anti H. pylori activity [65]. The ointment prepared from the peel extract accelerated wound healing and exhibited antioxidant properties in guinea pigs [66]. The tannins from fruit prevented formation of gastric ulcer, increased NO level and secretion of adherent and free mucus, and exhibited antioxidant activity in gastric mucosa [69].
2.14. Vitis vinifera L. The seed demonstrated antioxidant activity in vitro [73]. The fruit skin and seed revealed anti  Fruit/polyphenol extract -

Aspirin-induced and pylorus ligation-induced GU
Rat ↓GU in both models, no effect on gastric juice secretion, inhibition of aspirin-induced lipid peroxidation, and ↓COX2 and HB-EGF mRNA and protein over expression [34] Fruit    H. Pylori effects [74,75]. Proanthocyanidin-rich extract from seed protected against acute and chronic gastric and intestinal oxidative injury through inhibition of lipid peroxidation and membrane microviscosity in gastric and duodenal membrane [78]. It showed higher gastroprotective and antioxidant activity compared to vitamin E and C [80]. The seed also exhibited protective effect against gastric ulcer in rat. Antioxidant activity and strong ability of procyanidins to bind protein covering the stomach surface may be responsible for this protective affect [79]. This protein elevates defense activity of gastric membrane. The seed showed wound healing properties via enhancing angiogenesis and antioxidant activity [81,83]. Resveratrol, a high abundant polyphenol in red grape fruits, suppressed H. pylori growth, H. pylori-induced interleukin-8 secretion, reactive oxygen species generation, and morphological changes in human gastric epithelial cells [76,77]. Resveratrol in low dose (2 mg/Kg) demonstrated ulcer healing activity but in high dose (10 mg/Kg) was ulcerogenic. The mechanism of ulcer healing activity in low dose is attributed to inhibition of neutrophil aggregation, stimulation of COX1, PG E 2 , and eNOS, and improvement of angiogenesis [82].

Discussion
In TIM, a wide range of medicinal plants have been proposed for the treatment of different gastrointestinal disorders like inflammatory bowel disease, irritable bowel disease, hemorrhoids, and PU [84][85][86][87]. In this paper, all of edible fruits and spices claimed to be efficacious in the management of PU were collected from TIM sources, and any scientific evidence that prove their efficacy was retrieved from electronic databases. These remedies have shown their effectiveness on PU via several mechanisms of action including PG enhancement, modulation of inflammatory mediators, and antioxidant, anti H. pylori, wound healing, cytoprotective, and antisecretory activities. Some of the investigated fruits and spices like Myristica fragrans, Phyllantus embelica. Vitis vinifera, and Punica granatum have shown their beneficial effects in PU by affecting various associated mechanisms. According to published investigations, these fruits and spices seem to be more effective in the management of PU than the other ones. In contrast, for some of these fruits and spices including Morus species, Cornus mas, Rhus cariaria, and Phoenix dactylifera, just one or two studies on the efficacy and relevant mechanisms have been executed. Advanced scientific studies for evaluation of these herbs on PU and their possible mechanisms are suggested. Despite many pieces of in vitro and in vivo evidence, no human study was found to confirm the effectiveness of investigated fruits and spices in PU. As shown in Table 1, the plants used in TIM for management of PU are from different families, and there is no exact relationship between the family of plants investigated and their efficacy. No potential side effects have been reported from these remedies. Studies on antiulcer activity of some of investigated fruits and spices have revealed controversial results. For example, stored rice bran oil has shown ulcerogenic activity. Whereas, fresh rice bran diet and rice diet have demonstrated anti-PU properties in animal models [52,53]. Fruit polyphenol extract of Malus domestica has ulcerogenic effect [27]. In contrast, fruit juice, flavonoids extract, and fruit methanol extract have shown gastroprotective activity in various animal models [30,31,34]. Despite different reports on protective activity of berberine, an active compound of Berberis vulgaris, against gastric ulcer [19,20], there is a report about dosedependent gastric ulcer inducing activity of this compound [21]. Some of the investigated remedies have shown conflicting results in different doses. Resveratrol, a highly abundant polyphenol in Vitis vinifera fruit, in low dose demonstrated ulcer healing activity but in high dose was ulcerogenic [82].
Overall, there are various edible fruits and spices in TIM for the management of PU which their efficacy had confirmed through various in vitro and in vivo studies. Because of the lack of human studies, it is recommended to conduct clinical trials to prove their efficacy and obtain more conclusive results.