ANTI-ULCEROGENIC EFFICACY AND MECHANISMS OF EDIBLE AND NATURAL INGREDIENTS IN NSAID-INDUCED ANIMAL MODELS.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of the most commonly used medicines and proven to be effective for certain disorders. Some people use NSAIDs on daily basis for preventive purpose. But a variety of severe side effects can be induced by NSAIDs. Studies have shown that edible natural ingredients exhibit preventive benefit of gastric ulcer. This paper reviews the efficacy and safety of edible natural ingredients in preventing the development of gastric ulcer induced by NSAIDs in animal models.
METHODS: A systematic literature search was conducted on PubMed, using the terms "herbal medicines" and "gastric ulcer", "herbal medicines" and "peptic ulcer", "food" and "peptic ulcer", "food" and "gastric ulcer", "natural ingredient" and "peptic ulcer", "natural ingredient" and "gastric ulcer", "alternative medicine" and "peptic ulcer", "alternative medicine" and "gastric ulcer", "complementary medicine" and "peptic ulcer", "complementary medicine" and "gastric ulcer" in papers published in English between January 1, 1960 and January 31, 2016, resulting in a total of 6146 articles containing these terms. After exclusion of studies not related prevention, not in NSAID model or using non-edible natural ingredients, 54 articles were included in this review.
RESULTS: Numerous studies have demonstrated that edible natural ingredients exhibit antiulcerogenic benefit in NSAID-induced animal models. The mechanisms by which edible, ingredient-induced anti-ulcerogenic effects include stimulation of mucous cell proliferation, antioxidation, inhibition of gastric acid secretion, as well as inhibition of H (+), K (+)- ATPase activities. Utilization of edible, natural ingredients could be a safe, valuable alternative to prevent the development of NSAID-induced gastric ulcer, particularly for the subjects who are long-term users of NSAIDs.

Introduction

NSAIDs have been widely used for centuries for the treatment and prevention of various disorders (Wright, 1995). The therapeutic benefits of NSAIDs include relief of fever, pain, inflammation and depression (Cilliers, et al., 2015; Cremonesi and Cavalieri., 2015; Enthoven, et al., 2016; Köhler, et al., 2014). Long term use of aspirin, a NSAID, reduces the risk of and mortality of cardiovascular diseases, ischemic stroke, colorectal cancer and myocardial infarction (Dehmer, et al., 2016). But, NSAIDs can also increase the risk of developing gastric ulcer, hemorrhagic stroke and GI bleeding (Dehmer, et al., 2016; García Rodríguez et al., 2001, 2004; Kang et al., 2011, 2012; Voutilainen et al.,2001; Yamagata and Hiraishi., 2007). Up to 13% of patients with gastric ulcer are NSAIDs users (Konturek, et al., 2003) while gastric ulcer is a risk factor of gastric cancer (Hansson et al., 1996; Molloy and Sonnenberg., 1997), and negatively impact the quality of patients’ life, the work productivity and medical burden (Barkun et al., 2010; Sonnenberg and Everhart., 1997). Thus, these harmful effects of NSAIDs refrain it from being widely used in preventing and treating certain diseases, which require long-term use of NSAIDs. Although esomeprazole and proton pump inhibitors can effectively prevent NSAIDs-induced side effects (Hsiao, et al., 2009; Scheiman, et al., 2013a, b; Sylvester, et al., 2013), these drugs can induce severe adverse events, including microscopic colitis (Masclee, et al., 2015; Verhaegh, et al., 2016), galactorrhea (Pipaliya, et al., 2016), and reduced bone mineral density (Ozdil, et al., 2013). In contrast, studies have demonstrated that edible, natural ingredients can effectively prevent the formation of gastric ulcer with fewer side effects in various animal models including NSAID-induced gastric ulcer, suggesting the potential utilization of these ingredients for preventing gastric ulcer for subjects who take NSAIDs for long-term. We summarize here the antiulcerogenic benefits of certain edible, natural ingredients and the mechanisms of their action in NSAID-induced model of gastric ulcer. Literature search terms and methods are detailed in Table 1

Table 1

Search Terms and Results

Search Term	Results	Exclusion	Number of Papers Reviewed
Alternative medicine, peptic ulcer	690	Full paper is not available online; Not related prevention; Not in NSAID-induced gastric ulcer model; Using non-edible natural ingredients; Animal procedure was not detailed enough to determine the dosage and pretreatment time.	54
Alternative medicine, gastric ulcer	652
Chinese Medicine, gastric ulcer	208
Chinese Medicine, peptic ulcer	257
Complementary medicine, peptic ulcer	568
Complementary medicine, gastric ulcer	557
Food, peptic ulcer	1598
Food, gastric ulcer	1444
Herbal medicine, gastric ulcer	88
Herbal medicine, peptic ulcer	83
Natural ingredient, peptic ulcer	0
Natural ingredient, gastric ulcer	1
Total	6146

Efficacy

Although no data are available from human study, the antiulcerogenic benefits of edible, natural ingredients have been well demonstrated in animal models, as summarized in Table 2. Both aerial parts and fruits of trichosanthes cucumerina are edible, particularly in Asia. Study demonstrated that orally given 750 mg/kg body weight of trichosanthes cucumerina extract induced an 88% reduction in the numbers of haemorrhagic lesions caused by indomethacin in rats. The efficacy was comparable to that induced by conventional drug, cimetidine (100 mg/kg) (Arawwawala et al., 2010). Likewise, asparagus racemosus Willd is a common vegetable. In comparison to indomethacin alone, concurrently oral administrations of asparagus racemosus Willd extract at a daily dose of 100 mg/kg body weight with indomethacin for 15 days reduced ulcer index by over 80%, which was comparable to that induced by ranitidine at a daily dose of 30 mg/kg body weight (Bhatnagar and Sisodia., 2006). Moreover, Phyllanthus emblica fruit is commonly edible and available in Asia. Prior to induction of gastric ulcer with indomethacin, orally given Phyllanthus emblica fruit extract for 10 days caused a dose-dependent inhibition of ulcer index (Bandyopadhyay et al., 2000). Similarly, orally given pomegranate extract (500 mg/kg) 4 hours prior to aspirin administration induced an over 70% inhibition of ulcer index (Ajaikumar et al., 1997). Furthermore, edible natural ingredients also prevent the development of gastric ulcer in rats with diabetes, which is a risk factor for gastric ulcer (Masuda et al., 1976; Duggan et al., 1992). Pimple et al. showed that co-administrations of methanolic extract of Luffa acutangula fruits and aspirin could significantly lowered ulcer index in diabetes rats in comparison with aspirin alone (Pimple et al., 2012). Not all edible, natural ingredients display the preventive efficacy in a dose-dependent manner. It has been demonstrated that methanolic extract of Mouriri pusa at a dose of 250 mg/kg body weight lowered ulcer lesion index by 34% while 1000 mg/ kg body weight only induced a 7% inhibition of ulcer lesion index (Andreo et al., 2006). In addition, the inhibitory efficacy of Arctium lappa L.leaves is lower at the dose of 200 mg/kg body weight than at 50 mg/kg (de Almeida et al., 2012). Therefore, caution should be taken when determining what dose should be used because the efficacy of certain ingredients not always positively correlates with the dosage.

Table 2

Edible Natural Ingredients That Prevent the Development of NSAID-Induced Gastric Ulcer

Natural Ingredients	Species	Pretreatment Time	Herbal Ingredient		Positive Control		References
			Dose (mg/kg body weight)	Inhibition (%)	Dose (mg/kg body weight)	Inhibition (%)
Leaves of Mouriri pusa	Mouse	30 min	250	51	30	49	(Andreo et al.,2003)
			500	60
			1000	65
Trichosanthes cucumerina (aerial parts)	Rat	1 Hr after	750	88	100	90	(Arawwawala et al., 2010)
Musa sapientum var. paradisiaca fruits	Rat	3 days with NSAID	500	68	N/D		(Goel et al., 1985,1986,2001; Lewis et al., 1999)
Phyllanthus emblica fruits	Rat	10 days	60	14	N/D		(Bandyopadhyay et al., 2000)
			80	36
			100	86
			120	87
Syngonanthus arthrotrichus Silveira	Rat	30 min	100	55	100	73	(Batista et al., 2004)
			250	32
Asparagus racemosus Willd.	Rat	15 days with NSAID	100	82	30	88	(Bhatnagar and Sisodia., 2006)
Ocimum basilicum (aerial parts)	Rat	3 days	4000	35[4], 37[5]	30	6	(Akhtar and Munir., 1989)
Solanum nigrum (aerial parts)				3[4], 23[5]
Brassica oleracea var. botrytis L. (aerial parts)				42[4], 3[5]
Brassica olerace var. acephala DC (leaves)	Rat	1 hr	25	15	100	81	(Lemos et al., 2011)
			50	64
			100	66
Combretum duarteanum Cambess (leaves)	Mouse	30 minn	62.5	1.3	100	54	(de Morais Lima et al., 2013)
			125	30
			250	42
			500	49
Ginseng	Mouse	1 hr	30	0	N/D		(Oyagi et al., 2010)
			100	Inhibition (N/Q)[1]
			300
Arctium lappa L. roots	Mouse	30 min	50	68	100	61	(de Almeida et al., 2012)
			100	60
			200	43
Fruit extract of Aegle marmelos Corr	Rat	14 days	250	93	N/D		(Singh et al., 2015)
				97	250	97	(Das and Roy., 2012)
Grape seed	Rat	6 days	100	97	0.05	99	(Abbas and Sakr., 2013; Kim et al., 2013)
			300	94
Garcinia kola Heckel seed	Rat	1 day	100	59	50	39	(Olaleye and Farombi., 2006)
		7 days		77
		45 min	200	69	10	84	(Onasanwo et al., 2011)
Petroselinum crispum (Mill.) (aerial parts)	Rat	30 min	1000	37	N/D		(Al-Howiriny et al.,2003)
			2000	46
			250	50			(Al-Howiriny et al.,2000)
			500	62
Amaranthus tricolor L. (leaves)			200	65[2], 54[3]	0.2	71	(Devaraj and Krishna., 2011)
Baccharis dracunculifolia (Essential Oil)	Rat	1 hr	50	80	100	42	(Massignani et al., 2009)
			250	77
			500	75
Extract of Brazilian green propolis	50	2	50				(Barros et al., 2008; de Barros et al., 2007)
	250	6
	500	55
Fish oil	Rat	30 min	5 ml	74	N/D		(al-Harbi et al.,1995)
			10 ml	79
			5 ml	32
Evening primrose oil			10 ml	89			(al-Shabanah., 1997)
Eriobotrya japonica seed	Rat	14 days	1x	52	25	69	(Yokota et al., 2008 and 2011)
			3x	71
			5x	31
Glycine max L. grains	Rat	7days	250	26	20	95	(Kumar et al., 2013)
			500	44
Bauhinia purpurea leaves	Rat	30 min	100	64[4],31[5,7]	30	100	(Hisam et al., 2012; Zakaria et al., 2011, 2012)
			500	55[4],51[5], 24[7]
			1000	39[4],47[5], 59[7]
Elettaria cardamomum Maton. fruits	Rat	30 min	12.5[8]	86	50	69	(Jamal et al., 2006)
			12.5[9]	97
			25-50[9]	100
			450[10]	53
			500[5]	77
Opuntia ficus-indica var. Saboten stem	Rat	30 min	200	65	50	86	(Lee et al., 2002)
			600	58
Luffa acutangula fruits	Rat	21 days With NSAID	100-400[4]	6-19	2.5	75	(Pimple et al., 2012)
			100-400[5]	21-60
Citrus lemon Burm. fruits	Rat	30 min	33	37[11]	100	67	(Rozza et al., 2011)
			177	50[12]
			250	98[13]
Kaempferia parviflora	Rat	60 min	30	90	100	98	(Rujjanawate et al.,2005)
			60	97
			120	95
Morin	Rat	30 min i.p	50	≈85	ND		(Singh et al., 2015b)
Seeds of Azadirachta indica	Rat	45 min	20	53	10	58	(Singh et al., 2015a)
Extract of Punicagranatum L. Fruits	Rat	60 min	250	22	50	45	(Ajaikumar et al., 2005)
			500	74
Condonopsis pilosula roots	Rat	60 min	5000	40	67.5	68	(Wang et al., 1997)
			10000	38
Potentilla fulgens Wall. ex Hook roots	Rat	7 days	100	27	50	71	(Laloo et al., 2013)
			200	38
			400	48
Extract of Croton zehntneri leaves	Rat	60 min	30	34	10	61	(Coelho-de-Souza et al., 2013)
			100	69
			300	79
Ginger powder	Rat	0	200	>90	ND		(Wang et al., 2011)
Mixture of Blumea balsamifera leaves, Curcuma domestica L. and Ammomum compactum S. pods	Rat	7 days With NSAID	690-890	90-100	360	≈78	(Mutmainah et al., 2014)
Isoliquiritigenin from Glycyrrhiza glabra	Rat	3 days	100	75	30	65	(Choi et al., 2015)
Trigonelline from Trigonella foenum-graecum L.	Rat	30 min	45	81.71	40	≈85	(Antonisamy et al.,2016)
Berberis vulgaris	Mouse	7 days With NSAID	900	100	20	100	(Majeed et al., 2015)
Extract of Azadirachta indica Seeds	Rat	45 min	20	56	10	58	(Singh et al., 2015)
Extract of Carica papaya seed	Rat	14 days	200	43	200	48	(Oloyede et al., 2015)
Extract of cochinchina momordica seed	Rat	60 min	200	≈60	ND		(Lim et al., 2014)
Essential oil from Citrus aurantium	Rat	30 min	7.5	74	100	99	(Bonamin et al., 2014)

N/Q: not quantitated;

ethanol extract;

ethy acetate extract;

water extract;

methanol extract; 6 undefined concentration;

chloroform extract;

essential oil;

petroleum ether soluble fraction;

petroleum ether insoluble fraction;

β-pinene

limonene;

Citrus lemon.

In addition to vegetables and fruits, certain edible oils also exhibit gastroprotective benefit. For instance, 1 hour prior to induction of ulcer by indomethacin orally given essential oil from Baccharis dracunculifolia at a single dose of 50 mg/kg body weight induced an 80 inhibition of ulcer index while oral cimetidine at a dose of 100 mg/kg body weight only caused 42% inhibition of ulcer index (Massignani et al., 2009). Evening primrose oil, another edible oil, can also dose-dependently prevent the development of gastric ulcer induced by either aspirin or indomethacin (al-Shabanah., 1997). Even the fish oil, one of the most common dietary supplements, displays antiulcerogenic benefit in aspirin- and indomethacin-induced gastric ulcer models of rats (al-Harbi et al., 1995). Moreover, soybean, a commonly consumed food, is a potent antiulcerogenic agent, too. Kumar et al. reported that once daily oral soybean paste 30 min prior to each aspirin administration for 7 days lowered gastric ulcer scores by over 40% in rats (Kumar et al., 2013). Furthermore, oral administration of extract from a mixture of Blumea balsamifera leaves, Curcuma domestica L. and Ammomum compactum S. pods almost completely prevented the development of aspirin-induced gastric ulcer (Mutmainah et al., 2014). Not only oral administration, but also intraperitoneal injection of food extract shows antiulcerogenic benefit. For example, morin is a flavonoid commonly found in almond, osage orange and fig. 30 min prior to induction of ulcer with indomethacin in rats, intraperitoneal injection of morin at a single dose of 50 mg/kg body weight reduced ulcer lesion index by over 80% (Singh et al., 2015).

It is worth noting that the preparation methods can affect the antiulcerogenic efficacy of certain edible ingredients. For instance, dichloromethane extract of Mouriri pusa leaves at a dose of 250mg/kg body weight induced a 51% inhibition of ulcer lesion index while the same dose of methanolic extract caused 34% inhibition (Andreo et al.,2006). Likewise, aqueous extract of Solanum nigrum at a dose of 4g/kg exhibited no preventive effect in an animal model of aspirin-induced gastric ulcer while the same dose of methanolic extract induced an over 20% inhibition of ulcer index (Akhtar and Munir., 1989). Similarly, methanolic extract of Luffa acutangula is more effective than its aqueous extract (Rozza et al., 2011). In contrast, aqueous extract of Brassica oleracea, but not methanolic extract, induced a 42% inhibition of ulcer index (Akhtar and Munir., 1989). However, both aqueous and methanolic extracts of Ocimum basilicum, exhibited a similar efficacy of antiulcerogenesis (Akhtar and Munir., 1989). Therefore, special attention should be paid to the preparation methods when using these ingredients.

Safety

In addition to soybean and common nutrient supplements such as fish oil and evening primrose oil, other edible, natural ingredients, also are generally safe. For instance, a single of 500 mg/kg body weight methanolic extract of Mouriri pusa could effectively lower ulcer lesion index (Andreo et al., 2006) while orally given a single dose of 5000 mg/kg body weight did not cause any signs or symptoms of acute toxicity during a 14-day follow-up period. No lesion or pathological changes occurred in internal organs of the mice (Andreo et al., 2006). Moreover, no adverse event was observed in rats 14 days after single oral administration of alcoholic extract of Brassica oleracea var. acephala DC leaves, a vegetable, at a dose of 2g/kg body weight (Lemos et al.,2011). The LD50 value for Petroselinum crispum (Mill.) extract is 13g/kg body weight in rats 3 days after a single intraperitoneal injection (Al-Howiriny et al.,2003). All these evidences indicate that edible, natural ingredients are safe for preventing the development of gastric ulcer.

Mechanisms

While NSAIDs can inhibit inflammation, they also induce the production of proinflammatory cytokines via activation of 5-lipoxygenase pathway (Sinha et al., 2013). NSAIDs can also inhibit prostaglandin E2 synthesis and induce oxidative stress (McAnulty et al., 2007; Sinha et al., 2013), eventually leading to the development of gastric ulcer (Sinha et al., 2013; Tandon et al., 2004). The mechanisms by which edible, natural ingredients display antiulcerogenic benefit include anti-inflammation, antioxidaion, stimulation of prostaglandin E2, and inhibition of acid secretion, etc. (Table 3).

Table 3

The Mechanisms That Edible Natural Ingredients Prevent Gastric Ulcer

Natural Ingredients	Mechanisms	Reference
Trichosanthes cucumerina (aerial parts)	↓ Acid secretion, ↑ Mucus content, Antihistamine	(Arawwawala et al., 2010)
Musa sapientum var. paradisiaca fruits	Anti-oxidative properties, ↑ Proliferation	(Goel et al., 1986,2001)
Phyllanthus emblica fruits	Anti-oxidative properties, ↑ Mucus content	(Bandyopadhyay et al., 2000)
Syngonanthus arthrotrichus Silveira	↓ Acid secretion, ↑ Mucus content	(Batista et al., 2004)
Asparagus racemosus Willd.	Anti-oxidative properties, ↓ Acid secretion, ↑ Mucus content	(Bhatnagar et al., 2005; Bhatnagar and Sisodia., 2006; Sairam et al., 2003)
Ocimum basilicum (aerial parts)	↓ Acid secretion, ↓ Pepsin levels	(Akhtar and Munir., 1989; Singh 1999)
Solanum nigrum (aerial parts)	↓ Acid secretion, ↓ Pepsin levels, ↓ H+/K+ ATPase activity	(Akhtar and Munir., 1989; Jainu and Devi., 2006)
Brassica oleracea var. botrytis Li. (aerial parts)	↑ Mucus content, ↓Pepsin levels	(Akhtar and Munir., 1989)
Brassica oleracea var. acephala DC (leaves)	↓ Acid secretion, ↑ Mucus content	(Lemos et al., 2011)
Ginseng	Anti-oxidative properties, ↑ Mucus content, ↓ H+/K+ ATPase activity	(Jeong., 2002; Oyagi et al., 2010)
Arctium lappa L. roots	Anti-oxidative properties, ↓ Acid secretion, ↓ H+/K+ ATPase activity	(de Almeida et al., 2012; Dos Santos et al., 2008)
Fruit extract of Aegle marmelos Corr	Anti-oxidative properties, ↓ Acid secretion, ↑ Mucus content	(Das and Roy., 2012; Singh et al., 2015)
Grape seed	↓ Inflammation	(Abbas and Sakr., 2013; Kim et al., 2013)
Garcinia kola Heckel seed	Anti-oxidative properties, ↓ Acid secretion, ↓ H+/K+ ATPase activity	(Olaleye and Farombi., 2006; Onasanwo et al., 2011)
Petroselinum crispum (Mill.) (aerial parts)	Anti-oxidative properties, ↓ Acid secretion, ↑ Mucus content	(Al-Howiriny et al.,2000; Al-Howiriny et al.,2003)
Baccharis dracunculifolia (Essential Oil)	↓ Acid secretion	(Lemos et al., 2007;Massignani et al., 2009)
Extract of Brazilian green propolis	↓ Acid secretion	(Barros et al., 2008; de Barros et al., 2007)
Fish oil	↓ Acid secretion	(al-Harbi et al.,1995)
Evening primrose oil	↓ Acid secretion	(al-Shabanah., 1997; Prichard et al., 1988)
Eriobotrya japonica seed	Anti-oxidative properties, ↑ Mucus content, ↑PGE2	(Yokota et al., 2008 and 2011)
Bauhinia purpurea leaves	↓ Acid secretion, ↑ Mucus content↓ Inflammation	(Hisam et al., 2012; Zakaria et al., 2011, 2012)
Morin	Anti-oxidative properties,↓Inflammation	(Singh et al., 2015b)
Seeds of Azadirachta indica	↓ Acid secretion, ↑ PGE2, ↓ H+/K+ ATPase activity	(Singh et al., 2015a)
Extract of Punicagranatum L. Fruits	Anti-oxidative properties	(Ajaikumar et al., 2005)
Condonopsis pilosula roots	↓ Acid secretion	(Wang et al., 1997)
Potentilla fulgens Wall. ex Hook roots	Anti-oxidative properties, ↓ Acid secretion, ↑ Proliferation, ↓ H+/K+ ATPase activity, ↓ Histamine content	(Laloo et al., 2013)
Extract of Croton zehntneri leaves	↑ Mucus content	(Coelho-de-Souza et al., 2013)
Ginger powder	↓ Inflammation[1]	(Wang et al., 2011)
Mixture of Blumea balsamifera leaves, Curcuma domestica L. And Ammomum compactum S. pods	↓ Inflammation	(Mutmainah et al., 2014)
Trigonelline from Trigonella foenum-graecum L.	↓ Inflammation, ↑ PGE2, Anti-oxidative properties	(Antonisamy et al.,2016)
Extract of cochinchina momordica seed	↓ Inflammation, Anti-oxidative properties	(Lim et al., 2014)
Essential oil from Citrus aurantium	↑ PGE2, Anti-oxidative properties	(Bonamin et al., 2014)

Lowered plasms cytokines; ↓: decrease; ↑:increase.

a. Antioxidation

The role of oxidative stress in the pathogenesis of gastric ulcer is well recognized while NSAIDs can induce oxidative stress in various tissues including gastric mucosa (Adachi et al., 2007; Bhattacharyya et al. 2014; Ghosh et al., 2015; Hiraishi et al., 2000; Tandon et al., 2004). Accordingly, employment of antioxidants could benefit gastric ulcer. Studies have shown that the antioxidant property of certain natural ingredients can contribute to their preventive benefits in the development of gastric ulcer in various animal models (Alimi et al., 2010, 2011, 2013;

Nartey et al., 2012; Repetto et al., 2002). Bhatnagar et al. reported that oral administration of Asparagus racemosus extract at a daily dose of 100mg/kg body weight for 15 days did not only increase the activities of superoxide dismutase (SOD) and catalase (CAT), but also the content of ascorbic acid in both the stomach and liver to the levels comparable to ranitidine. In addition, the levels of malondialdehyde (MDA), a product of lipid peroxidation, were also significantly reduced in indomethacin-induced model of gastric ulcer (Bhatnagar et al., 2005). Orally given aqueous extract of Aegle marmelos fruits at a daily dose of 250 mg/kg body weight for 14 days significantly increased the content of reduced glutathione (GSH), and the activities of SOD and CAT in an animal model of aspirin-induced gastric ulcer (Das and Roy., 2012). Even only one hour prior to induction of gastric ulcer with aspirin, oral administration of extract of Punicagranatum L. fruits could dramatically increase the levels of SOD, CAT and glutathione peroxidase in the stomach in comparison with rats treated with aspirin alone (Ajaikumar et al., 2005). Extracts of both ginseng and Arctium lappa L. roots exhibit free-radical scavenging activity (Dos Santos et al., 2008; Jeong., 2002). Taken together, antiulcerogenic benefit of certain edible, natural ingredients could be attributed to their antioxidant property.

b. Inhibition of acid secretion

Increased acid secretion in part plays a role in the pathogenesis of gastric ulcer (Abdul-Aziz., 2011). Accordingly, sodium bicarbonate, a base, has been used to relieve the symptoms of gastric ulcer. Studies have shown that some edible natural ingredients prevent the development of gastric ulcer via inhibition of acid secretion in various animal models, including NSAID-induced gastric ulcer. Orally given Asparagus racemosus Willd. at a daily dose of 100 mg/kg body weight for 15 days markedly decreased the volume and acidity of gastric juice in a model of gastric ulcer induced by indomethacin (Bhatnagar et al., 2005). Likewise, oral administration of extract of Garcinia kola Heckel Seeds at a daily dose of 100 mg/kg body weight for 3 days induced an over 47% reduction in the volume of gastric juice and an over 45% increase in pH of the gastric juice (Olaleye and Farombi., 2006). There are several mechanisms involved in the inhibition of acid secretion induced by edible, natural ingredients. First, the enzyme H+, K+-ATPase in the gastric parietal cells is known to transports the H+ against a concentration gradient, leading to acid secretion [110]. Extracts of certain ingredients such as ginseng, Arctium lappa L. roots and Garcinia kola Heckel seeds are potent inhibitors of H+, K+-ATPase (Dos Santos et al., 2008; Onasanwo et al., 2011; Oyagi et al., 2010). For example, the IC50 of Arctium lappa L. root extract for H+, K+-ATPase is 53μg/ml (Dos Santos et al., 2008). IC50 of Garcinia kola Heckel seed extract is 43.8μg/ml while IC50 of omeprazole, a conventional inhibitor, is 32.3μg/ml (Onasanwo et al., 2011). Second, histamine stimulates acid secretion while NSAIDs enhance the effect of histamine on acid secretion (Schwartzel et al., 1984; Shamburek and Schubert., 1992). Studies have demonstrated that oral administration of the extract of Trichosanthes cucumerina (aerial parts) was more effective then chlorpheniramine in reduction of wheal size induced by subcutaneous injection of histamine, suggesting antihistamine effect (Arawwawala et al., 2010). In addition, pre-feed rats with oral Potentilla fulgens Wall. ex Hook extract for 7 days significantly lowered histamine levels in the stomach tissue in a model of gastric ulcer (Laloo et al., 2013). Third, prostaglandin E2 inhibits acid secretion, and to protect stomach from the damage induced by indomethacin (Befrits and Johansson., 1985; Robert et al., 1981; Takeuchi., 2014). But NSAIDs lower prostaglandin E2 levels (el-Bayar et al., 1985). Inhibition of acid secretion by some ingredients could be through stimulating prostaglandin E2 production. Yokota et al. demonstrated that pre-feed rat with Eriobotrya japonica seed extract for 14 days increased prostaglandin E2 levels by 95% in stomach tissue of indomethacin-induced ulcer (Yokota et al., 2011). Orally given 20 mg/kg body weight of Azadirachta indica seed extract is more potent than omeprazole (10mg/kg body weight) in elevation of prostaglandin E2 content in stomach tissue of aspirin-induced ulcer (Singh et al., 2015). Fourth, gastrin, a gastrointestinal hormone, can stimulate acid secretion independently or via histamine (Soll and Walsh., 1979). Treatment of rats with oral Solanum nigrum fruit extract dramatically lowered plasma levels of gastrin (Jainu and Devi., 2006). Additionally, serotonin can inhibit acid secretion (Bech., 1986). Treatment of rats with the extract of Aegle Marmelos fruits for 14 days could increase the serotonin content by 32% over aspirin treatment alone in an aspirin-induced gastric model (Singh et al., 2015). Collectively, edible, natural ingredients can inhibit H+, K+-ATPase activity, gastrin and histamine production while increase serotonin and prostaglandin E2 levels, leading to inhibition of acid secretion.

c. Inhibition of inflammation

Another feature of gastric ulcer is gastric inflammation, which is attributed in part to the NSAID-induced gastric ulcer (Sinha et al., 2013). Some ingredients that exert antiulcerogenic activity inhibit inflammation. In addition to an over 80% reduction in serum IL-1β levels, pre-feed rats with grape seed extract at a daily dose of 100mg/kg body weight for 6 days lowered serum TNFα to an undetectable level in indomethacin-induced gastric ulcer model (Kim et al., 2013). Likewise, co-administrations of ginger powder at a dose of 200 mg/kg body weight with aspirin for 4 hours induced an over 40% reduction in plasma TNFα and IL-1β levels in comparison with aspirin alone (Wang et al., 2011). Moreover, edible ingredients also inhibit inflammatory cell infiltration. 30 min prior to induction of gastric ulcer with indomethacin, pre-feed rats with extract of Bauhinia purpurea leaves provoked 100% inhibition of leukocytes infiltration into gastric wall (Hisam et al., 2012). Similarly, both eosinophil and mast cell infiltration into mucosal wall were inhibited by oral administration of extract of a mixture containing Blumea balsamifera leaves, Curcuma domestica L. and Ammomum compactum S. pods 10 min prior to induction of gastric ulcer with aspirin (Mutmainah et al., 2014). Consistent with anti-inflammation, oral mourin also reduced the expression levels of Intercellular adhesion molecule-1 in gastric mucosa in a model of aspirin-induced gastric ulcer (Sinha et al., 2015). Thus, inhibition of inflammation is another mechanism by which edible, natural ingredients prevent the development of NSAID-induced gastric ulcer.

d. Others Mechanisms

Heat shock protein 70(HSP70) is constitutively expresses in gastric mucosal cells. HSP70 plays a crucial role in protecting mucosal cells against NSAID-induced damage (Choi et al., 2009). Either overexpression or upregulation of HSP70 inhibits the gastric damage caused by indomethacin (Suemasu et al., 2009). Some edible ingredients protect stomach against NSAID-induced damage via upregulation of HSP70 expression. Studies have demonstrated that pretreatment of rats with ginger powder, or extract of Citrus lemon Burm. fruits or mourin significantly increased gastric HSP70 expression in NSAID-induced gastric ulcer [Rozza et al., 2011; Salah Khalil., 2015; Sinha et al., 2015).

One of the mechanisms that NSAIDs induce gastric damage is the reduction in mitochondrial dehydrogenase activity, leading to excessive oxidative stress (Maity et al., 2009). Morin can overcome the reduction in the mitochondrial dehydrogenase activity induced by indomethacin (Sinha et al., 2015). Other mechanisms of edible, natural ingredients-induced gastric protection include the reduction in cell shedding and microvascular permeability (Laloo et al., 2013), upregulation of mucus content (Arawwawala et al., 2010; Bandyopadhyay et al., 2000; Batista et al., 2004) and mucosal glycoproteins (Mohan Kumar et al., 2006; Pimple et al., 2012), as well as mucosal cell proliferation (Laloo et al., 2013).

Conclusions

Edible, natural ingredients are effective for preventing the development of gastric ulcer induced by NSAIDs via divergent mechanisms. Because edible, natural ingredients are safe and widely available, they could be an optimal regimen for antiulcerogenesis, particularly for subjects who require long-term NSAID treatments. However, due to the lack of human clinical data and public awareness, these edible natural ingredients have not been widely deployed in clinical setting. Further clinical studies are required to validate the efficacy and safety of these ingredients for gastric ulcer.

superoxide dismutase

glutathione

malondialdehyde

nonsteroidal anti-inflammatory drugs

Authors’ Contributions: WB originated the concept, collected data and wrote draft; LH wrote draft; MQM critically reviewed the manuscript.

All Authors declare no conflicts of interest