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Secondary metabolites for antiulcer activity Parag Jain
a
a
Department of Pharmacology, Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya, Koni, Bilaspur, Chhattisgarh495009, India Published online: 29 Apr 2015.
Click for updates To cite this article: Parag Jain (2015): Secondary metabolites for antiulcer activity, Natural Product Research: Formerly Natural Product Letters, DOI: 10.1080/14786419.2015.1036269 To link to this article: http://dx.doi.org/10.1080/14786419.2015.1036269
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Natural Product Research, 2015 http://dx.doi.org/10.1080/14786419.2015.1036269
REVIEW Secondary metabolites for antiulcer activity Parag Jain* Department of Pharmacology, Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya, Koni, Bilaspur, Chhattisgarh 495009, India
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(Received 12 January 2015; final version received 15 March 2015)
Peptic ulcers are open sores or erosions in the lining of either the duodenum (duodenal ulcers) or the stomach (gastric ulcers). Peptic ulcer, which is mainly caused by bacterial attack or excess of acid secretion, can be cured effectively by these isolated plant compounds. In this present scenario, demand for herbal medicines are increasing due to easy availability in surrounding place at low cost. This review article is all about such isolated plant compounds such as alkaloids, flavonoids and terpenoids. Various plants have been used as folk medicine by the people of rural area, which shows significant effect against peptic ulcer. Further study should be conducted upon these herbal plants because there is possibility for minimising the adverse effect caused by the present antiulcer drugs. Keywords: peptic ulcer; secondary metabolites; alkaloids; flavonoids; terpenoids
Introduction Plants have been the basis for medical treatments through much of human history, and such traditional medicine is still widely practiced today. Modern medicine now includes plantderived compounds as the basis for evidence-tested pharmaceutical drugs. All plants produce chemical compounds as part of their normal metabolic activities. Plants synthesise a bewildering variety of phytochemicals, which are mostly derivatives of biochemical motifs. These phytochemicals include primary metabolites such as sugars and fats, which are found in all plants, and secondary metabolites which are found in a smaller range of plants having alkaloids, glycosides, resins, terpenoids, flavanoids and tannins, serving a more specific function (Meskin et al. 2002). It is these secondary metabolites and pigments that can have therapeutic actions in humans and which can be refined to produce drugs such as reserpine from roots of Rauwolfia
*Email: [email protected] q 2015 Taylor & Francis
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serpentina, vincristine from leaves of Vinca rosea and silymarin from leaves of Silybum marianum. Some secondary metabolites are toxins used to deter predation and others are pheromones used to attract insects for pollination. For over a century, peptic ulcer disease (PUD) has been one of the leading causes of gastrointestinal surgery, with high morbidity and mortality rates worldwide. The prevalence of gastrointestinal ulcers differs around the world: duodenal ulcers are dominant the Western populations and gastric ulcers are more frequent in Asia. As the prevalence of this disease increases over time, one would expect peptic ulcers to continue to have a significant global impact in the basic health and economic systems and in patient’s life quality (Yuan et al. 2006). Ulcer develops when there is an imbalance between the ‘aggressive’ and ‘protective’ factors at the luminal surface of the epithelial cells. Aggressive factors include Helicobacter pylori, hydrochloric acid (HCl), pepsins, nonsteroidal anti-inflammatory drugs (NSAIDs), bile acids, ischemia, hypoxia, smoking and alcohol, while defensive factors include bicarbonate, mucus layer, mucosal blood flows, prostaglandins (PGs) and growth factors (Harold et al. 2007). Ulcers cause gnawing, burning pain in the upper abdomen. These symptoms frequently occur several hours following a meal, after the food leaves the stomach but while acid production is still high. Instead of pain, some patients experience intense hunger or bloating. Other patients have no pain but have black stools, indicating that the ulcer is bleeding. Bleeding is a very serious complication of ulcers (Mahajan & Sanghai 2009). Herbs are a way to strengthen and tone the body’s system and prevent diseases. Therefore an attempt has been made to explore importance of active phytoconstituents in treatment of peptic ulcer. Secondary metabolites Although there is a plethora of traditional plants with great therapeutic potential, the majority of medicinal plants have yet to be utilised on a large scale. One of the main reasons for this is the chemical variability inherent in plant-derived therapeutics. Many of the medically useful secondary metabolites produced by plants are the result of the latter’s response to stress (Gorelick & Nirit 2014). Secondary metabolites are those metabolites which are often produced in a phase of subsequent to growth, are produced by certain restricted taxonomic groups, have unusual chemicals structures, and are often formed as mixtures of closely related members of a chemical family. Plant secondary metabolism produces products that aid in the growth and development of plants but are not required for the plant to survive. In order for the plants to stay healthy, secondary metabolism plays a pinnacle role in keeping all plants’ systems working properly. A common role of secondary metabolites in plants is defence mechanisms. They are used to fight off herbivores, pests and pathogens (Pavarinia et al. 2012; Erb et al. 2013). Active secondary metabolites with anti-ulcer activity The natural active compound classes or secondary metabolites such as alkaloids, flavonoids, terpenoids and tannins have attracted researchers to investigate their chemical, toxicological and pharmacological features. In this context, the use of medicinal plants is in continuous expansion all over the world for the prevention and treatment of different pathologies, and natural products are recovering space and importance in the pharmaceutical industry as inspiring sources of new potentially bioactive molecules (Ziegler & Facchini 2008) (Doughari 2012). Alkaloids Alkaloids are the largest group of chemicals that contain ammonia compounds comprising basically nitrogen bases synthesised from amino acids. These compounds have few basic
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properties of alkaline in reaction and turning red litmus paper blue. In fact, one or more nitrogen atoms that are present in an alkaloid, typically as primary, secondary or tertiary amines, contribute to the basicity of the alkaloid. The degree of basicity varies considerably depending on the structure of the molecule and presence and location of the functional groups. They react with acids to form crystalline salts without the production of water. The plant-derived alkaloids in clinical use include analgesics such as morphine and codeine, muscle relaxant such as tubocurarine, antibiotics such as sanguinafine and berberine, anticancer agents such as vinblastine, antiarrythmics such as ajmaline, the pupil dilator – atropine – and the sedative – scopolamine. Alkaloids used for anti-ulcer activity are mentioned in Table 1 and their chemical constituents are illustrated in Figure 2.
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Flavonoids Flavonoids are important group of polyphenols widely distributed among the plant flora. Structurally, they are made of more than one benzene ring in its structure (a range of C15 aromatic compounds) and numerous reports support their use as antioxidants or free radical scavengers. The compounds are derived from parent compounds known as flavones. Over 4000 flavonoids are known to exist and some of them are pigments in higher plants. Quercetin, kaempferol and quercitrin are common flavonoids present in nearly 70% of plants (Figure 3). Other flavonoids include flavones, dihydroflavons, flavones, flavonols, anthocyanidins, proanthocyanidins, calchones and catechin and leucoanthocyanidins. Flavonoids against peptic ulcer are mentioned in Table 2.
Terpenes Terpenes are among the most widespread and chemically diverse groups of natural products. They are flammable unsaturated hydrocarbons, existing in liquid form commonly found in essential oils, resins or oleoresins. Terpenoids include hydrocarbons of plant origin of general
Figure 1. Factors involved in formation of ulcer.
Hirsutine
Eugenol Chromanone
Pithecolobine
b-carboline
Phyllanthine
Voacangine
Vinpocetine
2.
3. 4.
5.
6.
7.
8.
9.
15. Naringin
13. 7,8-Dihydro-8hydroxypalmatine 14. Taspine
11. Matrine and oximatrine 12. Canthin-6-one
10. Capsaicin
Reserpine
Isolated compound
1.
S. no. Family
Enantia Annonaceae chlorantha Oliver Croton lechleri Euphorbiaceae Mu¨ll. Arg., Mimosa pudica Fabaceae
Increase mucin secretion
Increase mucin secretion
Mode of action
Baumeister et al. (2003) Ozaki (1989)
Reference
AIU
AIU, PLIU
EIU, AAIU, PLIU AAIU
Lewis (1989)
Increase in the production of protective endogenous nitric De souza almeida oxide et al. (2011) Histamine H2 receptor blocking activity Tan & Nyasse (2000) Reducing myeloperoxidase activity, ulcer size, and Miller et al. (2000) bacterial content of the ulcer Increase in mucosal resistance Aly & Scand (1987)
Increase mucin secretion
Stimulate the synthesis of mucus Singh (1999) Reduction of malondialdehyde, reduced glutathione levels Lemos et al. (2012) in the gastric tissue EIU, SSIU H þ , K þ and ATPase inhibition Arumugam et al. (2011) PLIU, HIU Increase mucin secretion Dharmani et al. (2005) IIU, EIU, CRIU Enhancing mucosal protection possibly by mobilization of Okoli et al. (2009) endogenous prostaglandins EIU, IIU Physico– chemical re-enforcement of the gastric mucous Koroc et al. (2009) layer EIU, AAIU, Prostaglandinmediated mechanism Nosalova et al. PLIU (1993) EIU, AIU Reduction in mucosal mucus depletion Kang et al. (1995)
IIU, EIU EIU, IIU
EIU
SIU
Animal modela
Simaba ferruginea Simaroubaceae EIU
Capsicum annuum Solanaceae L. Berberis alkaloids Berberidaceae
Rauwolfia Apocynaceae serpentina Cocculus hirsutus Menisper maceae Mentha spicata L. Lamiacea Calophyllum Clusiaceae brasiliesnse Samanea saman Leguminoseae merr Desmodium Fabaceae gangeticum Phyllanthus niruri Euphorbiaceae Linn. Voacanga Apocynaceae Africana Vinca minorL. Apocynaceae
Plant name
Table 1. Alkaloids with antiulcer activity.
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Asteraceae
EIU, IIU, PLIU Enhanced mucus production and stimulate prostaglandin- Walber et al. (2005) E2 formation Euphorbiaceae PLIU, SSIU Increased gastric and duodenal alkaline secretion Kalimuthu et al. (2010) Trigonella foenum Papilionaceae EIU Decreased gastric acid secretion Toppo et al. (2009) graecum Centella asiatica Apiaceae EIU, AAIU, Strengthening of mucosal defensive factor Shakir et al. (2007) SIU, CRIU
Senecio brasiliensis Acalypha indica
Stress induced ulcer (SIU), Indomethacin induced ulcer (IIU), Pylorus ligation induced ulcer (PLIU), Histamine induced ulcer (HIU), Ethanol-acid induced ulcer (EIU), Acetic acid induced ulcer (AAIU), Cold resistant stress induced ulcer (CRIU), Swimming stress-induced ulcer (SSIU).
a
19. Hydrocotyline
18. Trigonelline
17. Acalyphine
16. Senecionine
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Figure 2. Chemical constituents of alkaloids.
formula (C5H8)n and are classified as mono, di, tri and sesquiterpenoids depending on the number of carbon atoms. Examples of commonly important monoterpenes include terpinen-4-ol, thujone, camphor, eugenol and menthol. Diterpenes (C20) are classically considered to be resins and taxol. Terpenoids are classified according to the number of isoprene units these are monoterpene (limonene), sesquiterpene (artemisinin), diterpene (forskolin), triterpene (a-amyrin), tetraterpene (b-carotene) and polymeric terpenoids (rubber). Different terpenoids used for anti-ulcer activity are shown in Table 3 and illustrated in Figure 4. Other secondary metabolites Apart from all above-mentioned plants there are few other species which also contain potent anti-ulcer activities. These are used equally for quick and safe recovery from peptic ulcer as mentioned earlier and the important ones are mentioned in Table 4. Cause of peptic ulcer Peptic ulcer describes a condition in which there is a discontinuity in the entire thickness of gastric or duodenal mucosa that persists as a result of acid and pepsin in the gastric juice. Though they can occur at any level of the alimentary tract that is exposed to hydrochloric acid and pepsin, they can occur most commonly (98 – 99%) in either duodenal or the stomach in the ratio of 4:1 (Harsh Mohan 2009). Peptic ulcer is caused due to several causes of abnormal acid secretion, abnormal mucosal defence, reflux of bile and pancreatic juice, genetic predisposition, microbial attack, etc. Various factors involved in the formation of ulcer are shown in Figure 1.
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Figure 3. Chemical constituents of flavonoids.
Genetic predisposition: Heredity has been postulated to play a possible role in the pathogenesis of ulcer. Several rare genetic syndromes are associated with peptic ulcer, e.g. multiple endocrine neoplasias (Jamal et al. 2006). Abnormalities in the secretion of acid and pepsin: Acid – pepsin appear to be important in the pathogenesis of gastric ulcer. However, in contrast to duodenal ulcer, gastric ulcer patients generally have acid secretory rates that are normal or reduced as compared with non-ulcer patients. (Jamal et al. 2006) Abnormalities of mucosal defence: Diminished blood flow may lead to cell injury and ulceration in some patients. Gastric mucosal ischemia is believed to be a factor in the pathogenesis of acute mucosal injury and decreased bicarbonate secretion is a possible cause for diminished mucosal defence. Delayed gastric emptying: Gastric emptying has been found to be delayed in gastric ulcer. Prolonged gastric emptying cause stasis and delayed clearing of duodenal contents that have refluxed into the stomach. This in turn could damage gastric mucosa, cause gastritis and lead to ulceration. Reflux of bile and pancreatic juice: Regurgitation of duodenal contents, especially those containing bile, may induce gastric mucosal injury and subsequent gastric ulceration. Emotional stress: Emotional stress may alter factors that maintain mucosal integrity and thereby ulcers develop because of decreased mucosal defence. Cycloxygenase-1 (COX-1) is constitutively expressed in the gastrointestinal tract in large quantities and has been suggested to maintain mucosal integrity through continuous generation of prostaglandins (Halter et al. 2001).
Kaempferol rhamnoside
Sophoradin (chalconoid) Luteolin
Myricetin
Taxifolin Pinostrobin
Naringenin
2.
3.
5.
6. 7.
8.
Urticaceae
Family
Sophora flavescens
Musa sapientum Vitis vinifera and Cinnamomum verum
12. Vexibinol
13. Leucocyanidin 14. Procyanidin
Musaceae Rosaceae and Lauraceae
Fabaceae
Guttiferae
Garcinia kola Heckel
11. Kolaviron
Rutaceae Cucurbitaceae Rubiaceae
Citrus paradisi
Increased mucosal content of prostaglandin-E2 Increased mucosal content
EIU, IIU, PLIU EIU, IIU PLIU, SSIU CRIU, AIU EIU, SSIU, PLIU IIU EIU
Coelho et al. (2009) Eugine et al. (2012)
Martin et al. (1994)
Calderon-Montan˜o et al. (2011), Barnaulov et al. (1984), Sumbul et al. (2011) Lira et al. (2012), Sasajima et al. (1978), Konturek et al. (1986) Ulubelen et al. (1979), Miean and Mohamed (2001), Barnaulov et al. (1982) Hossein Hosseinzadeh et al. (2002), Clelia Akiko Hiruma-Lima et al. (2005), Calvo et al. (2007) Abdelwahab et al. (2011) Kumar et al. (2011)
Gulcin et al. (2004)
Reference
Increase in mucus secretion Protection by radical scavenging activity on the stomach surface against radical injury
Inhibits gastric acid secretion
Prabha et al. (2011) Saito et al. (1998), Souquet et al. (1996)
Yamahara et al. (1990)
Inhibition of H(þ ) K(þ )-ATPase activity Onasanwo et al. (2011)
Increase the gastric defensive factors Reducing gastric secretion
Increase in mucus secretion Increased thiobarbituric acid reactive substances levels Increase in hexosamine levels
Caricaceae and RIU, SIU, Increased prostaglandin-E2 levels Euphorbiaceae EIU, IIU
Tamarindus indica Linn. Caesalpiniaceae PLIU Boesenbergia rotunda Zingiberaceae EIU
Carica papaya and Alchornea glandulosa
Matricaria chamomilla and Brassica oleracea
Mode of action
IIU, EIU, Inhibits histamine-induced gastric acid secretion PLIU, AIU RIU, EIU, Stimulate prostaglandin-E2 formation PLIU
Animal modela
PLIU, SIU Asteraceae and RIU Brassicaceae
Myrtaceae and Syzygium aromaticum and Phyllanthus emblica Euphorbiaceae L. Sophora tonkinensis Fabaceae
Urtica dioica
Plant name
9. Orientin Wilbrandia ebracteata 10. Proanthocyanidins Ixora Coccinea
4.
Quercetin
Isolated compound
1.
S. no.
Table 2. Flavonoids with antiulcer activity.
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IIU, EIU, CRIU EIU, IIU
Asteraceae Anacardiaceae
Mikania laevigata
Mangifera indica Linn.
EIU, IIU
EIU
CRIU, PLIU EIU
Asteraceae
Lamiaceae
Silybum marianum (L.) Asteraceae Gaertn. Alhagi maurorum Boiss. Leguminosae
Scutellaria baicalensis Georgi Ligularia stenocephala
Blockade of 5-HT3 receptors
Influence para-sympathetic secretion
Inhibitory mechanism of enzymatic peroxidation Blocks histaminergic receptor
Carvalho et al. (2007), Severi et al. (2009)
Bighettia et al. (2005)
Awaad amani et al. (2006)
Lastra et al. (1992)
Preventive induction of profuse apoptosis Park et al. (2004) in the stomach Decreased volume of gastric juice Lee et al. (2010)
Stress induced ulcer (SIU), Indomethacin induced ulcer (IIU), Pylorus ligation induced ulcer (PLIU), Histamine induced ulcer (HIU), Ethanol-acid induced ulcer (EIU), Acetic acid induced ulcer (AAIU), Cold resistant stress induced ulcer (CRIU), Swimming stress-induced ulcer (SSIU), Reserpine induced ulcer (RIU), Aspirin induced ulcer (AIU).
a
18. Chrysoeriol 7-Oxylosoid 19. 7-hydroxycoumarin 20. Mangiferin
16. Caffeoylquinic acids 17. Silymarin
15. Wogonin
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Terpinen-4-ol
Betulinic acid Oleanolic acid 1,8-cineole
Tagitinin C
Epoxy-carvone
Ginsenosides RB1 or panaxosides
Populnoic acid
2.
3. 4. 5.
6.
7.
8.
9.
Anethum graveolens Xylocarpus granatum
Alpinia oxphylla Zataria multiflora Amphipterygium adstringens Standl.
12. Gedunin
13. Nootkatone
14. Carvacrol
15. 3 a-hydroxy-masticadienonic acid
Austroplenckia populnea Azadirachta Indica
Kaempferia galangal and Anethum graveolens Panax ginseng
Tithonia diversifolia
Cryptomeria japonica and Croton cajucara Benth. Melaleuca bracteata F Melaleuca bracteata F Ocimum minimum and Alpinia galangal
Zingiber officinale
Plant name
11. Limonene
10. Nimbin
Zingiberene
Isolated compound
1.
S. no.
Table 3. Terpenoids with antiulcer activity.
Anacardiaceae
Lamiaceae
Zingiber aceae
Meliaceae
Apiaceae
Meliaceae
Celastraceae
EIU
AIU
CRIU, AIU, PLIU, HIU EIU
CRIU, IIU, EIU EIU
EIU, IIU, PLIU SIU
EIU, IIU
Zingiberaceae and Apiaceae Araliaceae
EIU
IIU IIU IIU, EIU
Reference
Inhibition of the gastric acid secretion Inhibition of the gastric acid secretion Increased prostaglandins and endogenous sulfhydryls
Arrieta et al. (2003)
Mohsen et al. (2005)
Yamahara et al. (1990)
Chioma et al. (2009), Parmar (1986) Matsunaga et al. (2000), Souza et al. (2011) Inhibition of gastric acid Adesanwo et al. (2009) Inhibition of gastric acid Adesanwo et al. (2009) Mucosal gastric protection by de Sousa Maia et al. reducing gastric secretion (2005), Chudiwal et al. (2010) Stimulating the mucosal defences Sa´nchez-mendoza et al. (2011) Bruna et al. (2011) Inhibition of the gastric acid production, stimulation of mucus production Increased mucus secretion Choon Sik Jeong et al. (2003) Improvement of mucosal Andrade et al. (2006) defensive factors inhibits H þ -K þ -ATPase Chattopadhyay et al. activity (2004) Mucosal protective and Panchaxari and antisecretory effects Dandagi (2008) Inhibition of H(þ ) K(þ )-ATPase Lakshmi et al. (2010) activity
Mode of action
PLIU, IIU Inhibition of gastric secretion protects gastroduodenal mucosa EIU, AIU, Inhibition of gastric juice SSIU secretion and pepsin activity
Animal modela
Asteraceae
Myrtaceae Myrtaceae Lamiaceae and Zizibereceae
Cupressae and Euphorbiaceae
Zizibereceae
Family
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Prumnopitys andina
20. Ferruginol
Rodrı´guez et al. (2006)
Kim et al. (2005)
Kumar et al. (2011) Jain and Surana (2009)
Inhibition of Helicobacter pylori De pasquale et al. growth (1995)
Stress induced ulcer (SIU), Indomethacin induced ulcer (IIU), Pylorus ligation induced ulcer (PLIU), Histamine induced ulcer (HIU), Ethanol-acid induced ulcer (EIU), Cold resistant stress induced ulcer (CRIU), Swimming stress-induced ulcer (SSIU), Aspirin induced ulcer (AIU).
a
Xanthophyllomyces dendrorhous
IIU, EIU
PLIU, EIU Decreased gastric fluid volume EIU Increased prostaglandin E2 content Phaffiarhodozyma EIU Eliminating free radical and improving local blood circulation of the ulcer Podocarpaceae EIU Increased prostaglandin E2 content
Combretaceae
Cedrus deodara Pinaceae Gymnosporia rothiana Celast raceae
Pteleopsis suberosa
19. Astaxanthin
16. 2a,3b,19a,23,24-pentahydroxy-11-oxoolean-12-en-28-oic acid 28-O-b-dglucopyranosyl ester 17. b-himachalene 18. b amyrin
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Ehtanone
Verbascoside Plastoquinones
3-(2-hydroxyphenyl)propanoic acid Arabinogalactans type II
Methyl jasmonate
Araloside Aescin
2.
3. 4.
5.
7.
8. 9.
Tectona grandis Sargassum micracanthum Cinnamomum cassia Cochlospermum tinctorium Jasminum grandiflorum Aralia elata Aesculus hippocastanum L.
Andrographis paniculata Annona squamosa
Plant name
Araliaceae Sapindaceae
Cochlospermaceae Oleaceae
Fabaceae
Verbenaceae Sargassaceae
Annonaceae
Acanthucece
Family
HIU, PLIU CRIU, PLIU
AIU
HIU, EIU
EIU, IIU
CRIU, AIU, PLIU, HIU CRIU, PLIU EIU
CIU
Animal modela
Inhibition of gastric juice secretion induced ulcer(rats)
Inhibition of gastric juice secretion and pepsin activity Reduction in gastric fluid volume,
Inhibited the secretion of gastric acid
Inhibition of H(þ) K(þ)-ATPase activity Increase of prostaglandin-E2 levels
Basolateral and brush border membrane bound enzyme activities Inhibition of H(þ) K(þ)-ATPase activity
Mode of action
Umamaheswari et al. (2007) Lee et al. (2005) (Marhuenda et al. 1994)
Nergard et al. (2005)
Tanaka et al. (1989)
Singh et al. (2010) Mori et al. (2006)
Saranya and Geetha (2011) Yadav et al. (2011)
Reference
Stress induced ulcer (SIU), Indomethacin induced ulcer (IIU), Pylorus ligation induced ulcer (PLIU), Histamine induced ulcer (HIU), Ethanol-acid induced ulcer (EIU), Acetic acid induced ulcer (AAIU), Cold resistant stress induced ulcer (CRIU), Swimming stress-induced ulcer (SSIU), Reserpine induced ulcer (RIU), Cysteamine induced duodenal ulcer (CIU), Hypothermic restraint-stress ulcer (HIU).
a
6.
Mucin
Isolated compound
1.
S. no.
Table 4. Other secondary metabolites with antiulcer activity.
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Figure 4. Chemical constituents of terpenoids.
Calcitonin gene-related peptide (CGRP), a neuropeptide, can also prevent gastric mucosal injury (Ohno et al. 2008). Role of microbes: The bacteria Helicobacter pylori have revolutionized the approach of peptic ulcer diseases and gastritis. Almost all patients with duodenal ulcer and 80% of patients with gastric ulcers are infected with H. pylori. The organism is also associated with chronic active gastritis (stomach inflammation) and may also play a role in non-ulcer dyspepsia (the belching and bloating symptoms of indigestion). H. pylori infection has also been associated with a slightly increased risk of gastric cancer. Conclusion According to the old hypothesis, acid secretion was thought to be the sole cause of ulcer-formation and reduction in acid secretion was thought to be the major approach towards therapy. However, in the light of recent evidences this concept has changed. Now, treatment of ulcer mainly targets the potentiating of the defensive system along with lowering of acid secretion. This article glows light on cause and use of herbal medicines to treat peptic ulcer. Secondary metabolites which are obtained from ancient traditional medicinal plants, which have been used in rural or distant areas for treatment of peptic ulcer; are far away from the present world. This review article included the use of secondary metabolites such as alkaloids, flavonoids and terpenoids from various plants shows significant effect on peptic ulcer with their chemical structure, experimental models and their mode of action. The provided data may be useful for treating peptic ulcer in further research and serve the mankind. Review criteria The original research articles were searched in the Google scholar and significant database collection of records and contents of medicinal plant research from online libraries. The last decade articles were selected to prepare this review.
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Disclosure statement No potential conflict of interest was reported by the author.
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Natural Product Research: Formerly Natural Product Letters Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/gnpl20
Secondary metabolites for antiulcer activity Parag Jain
a
a
Department of Pharmacology, Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya, Koni, Bilaspur, Chhattisgarh495009, India Published online: 29 Apr 2015.
Click for updates To cite this article: Parag Jain (2015): Secondary metabolites for antiulcer activity, Natural Product Research: Formerly Natural Product Letters, DOI: 10.1080/14786419.2015.1036269 To link to this article: http://dx.doi.org/10.1080/14786419.2015.1036269
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Natural Product Research, 2015 http://dx.doi.org/10.1080/14786419.2015.1036269
REVIEW Secondary metabolites for antiulcer activity Parag Jain* Department of Pharmacology, Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya, Koni, Bilaspur, Chhattisgarh 495009, India
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(Received 12 January 2015; final version received 15 March 2015)
Peptic ulcers are open sores or erosions in the lining of either the duodenum (duodenal ulcers) or the stomach (gastric ulcers). Peptic ulcer, which is mainly caused by bacterial attack or excess of acid secretion, can be cured effectively by these isolated plant compounds. In this present scenario, demand for herbal medicines are increasing due to easy availability in surrounding place at low cost. This review article is all about such isolated plant compounds such as alkaloids, flavonoids and terpenoids. Various plants have been used as folk medicine by the people of rural area, which shows significant effect against peptic ulcer. Further study should be conducted upon these herbal plants because there is possibility for minimising the adverse effect caused by the present antiulcer drugs. Keywords: peptic ulcer; secondary metabolites; alkaloids; flavonoids; terpenoids
Introduction Plants have been the basis for medical treatments through much of human history, and such traditional medicine is still widely practiced today. Modern medicine now includes plantderived compounds as the basis for evidence-tested pharmaceutical drugs. All plants produce chemical compounds as part of their normal metabolic activities. Plants synthesise a bewildering variety of phytochemicals, which are mostly derivatives of biochemical motifs. These phytochemicals include primary metabolites such as sugars and fats, which are found in all plants, and secondary metabolites which are found in a smaller range of plants having alkaloids, glycosides, resins, terpenoids, flavanoids and tannins, serving a more specific function (Meskin et al. 2002). It is these secondary metabolites and pigments that can have therapeutic actions in humans and which can be refined to produce drugs such as reserpine from roots of Rauwolfia
*Email: [email protected] q 2015 Taylor & Francis
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serpentina, vincristine from leaves of Vinca rosea and silymarin from leaves of Silybum marianum. Some secondary metabolites are toxins used to deter predation and others are pheromones used to attract insects for pollination. For over a century, peptic ulcer disease (PUD) has been one of the leading causes of gastrointestinal surgery, with high morbidity and mortality rates worldwide. The prevalence of gastrointestinal ulcers differs around the world: duodenal ulcers are dominant the Western populations and gastric ulcers are more frequent in Asia. As the prevalence of this disease increases over time, one would expect peptic ulcers to continue to have a significant global impact in the basic health and economic systems and in patient’s life quality (Yuan et al. 2006). Ulcer develops when there is an imbalance between the ‘aggressive’ and ‘protective’ factors at the luminal surface of the epithelial cells. Aggressive factors include Helicobacter pylori, hydrochloric acid (HCl), pepsins, nonsteroidal anti-inflammatory drugs (NSAIDs), bile acids, ischemia, hypoxia, smoking and alcohol, while defensive factors include bicarbonate, mucus layer, mucosal blood flows, prostaglandins (PGs) and growth factors (Harold et al. 2007). Ulcers cause gnawing, burning pain in the upper abdomen. These symptoms frequently occur several hours following a meal, after the food leaves the stomach but while acid production is still high. Instead of pain, some patients experience intense hunger or bloating. Other patients have no pain but have black stools, indicating that the ulcer is bleeding. Bleeding is a very serious complication of ulcers (Mahajan & Sanghai 2009). Herbs are a way to strengthen and tone the body’s system and prevent diseases. Therefore an attempt has been made to explore importance of active phytoconstituents in treatment of peptic ulcer. Secondary metabolites Although there is a plethora of traditional plants with great therapeutic potential, the majority of medicinal plants have yet to be utilised on a large scale. One of the main reasons for this is the chemical variability inherent in plant-derived therapeutics. Many of the medically useful secondary metabolites produced by plants are the result of the latter’s response to stress (Gorelick & Nirit 2014). Secondary metabolites are those metabolites which are often produced in a phase of subsequent to growth, are produced by certain restricted taxonomic groups, have unusual chemicals structures, and are often formed as mixtures of closely related members of a chemical family. Plant secondary metabolism produces products that aid in the growth and development of plants but are not required for the plant to survive. In order for the plants to stay healthy, secondary metabolism plays a pinnacle role in keeping all plants’ systems working properly. A common role of secondary metabolites in plants is defence mechanisms. They are used to fight off herbivores, pests and pathogens (Pavarinia et al. 2012; Erb et al. 2013). Active secondary metabolites with anti-ulcer activity The natural active compound classes or secondary metabolites such as alkaloids, flavonoids, terpenoids and tannins have attracted researchers to investigate their chemical, toxicological and pharmacological features. In this context, the use of medicinal plants is in continuous expansion all over the world for the prevention and treatment of different pathologies, and natural products are recovering space and importance in the pharmaceutical industry as inspiring sources of new potentially bioactive molecules (Ziegler & Facchini 2008) (Doughari 2012). Alkaloids Alkaloids are the largest group of chemicals that contain ammonia compounds comprising basically nitrogen bases synthesised from amino acids. These compounds have few basic
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properties of alkaline in reaction and turning red litmus paper blue. In fact, one or more nitrogen atoms that are present in an alkaloid, typically as primary, secondary or tertiary amines, contribute to the basicity of the alkaloid. The degree of basicity varies considerably depending on the structure of the molecule and presence and location of the functional groups. They react with acids to form crystalline salts without the production of water. The plant-derived alkaloids in clinical use include analgesics such as morphine and codeine, muscle relaxant such as tubocurarine, antibiotics such as sanguinafine and berberine, anticancer agents such as vinblastine, antiarrythmics such as ajmaline, the pupil dilator – atropine – and the sedative – scopolamine. Alkaloids used for anti-ulcer activity are mentioned in Table 1 and their chemical constituents are illustrated in Figure 2.
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Flavonoids Flavonoids are important group of polyphenols widely distributed among the plant flora. Structurally, they are made of more than one benzene ring in its structure (a range of C15 aromatic compounds) and numerous reports support their use as antioxidants or free radical scavengers. The compounds are derived from parent compounds known as flavones. Over 4000 flavonoids are known to exist and some of them are pigments in higher plants. Quercetin, kaempferol and quercitrin are common flavonoids present in nearly 70% of plants (Figure 3). Other flavonoids include flavones, dihydroflavons, flavones, flavonols, anthocyanidins, proanthocyanidins, calchones and catechin and leucoanthocyanidins. Flavonoids against peptic ulcer are mentioned in Table 2.
Terpenes Terpenes are among the most widespread and chemically diverse groups of natural products. They are flammable unsaturated hydrocarbons, existing in liquid form commonly found in essential oils, resins or oleoresins. Terpenoids include hydrocarbons of plant origin of general
Figure 1. Factors involved in formation of ulcer.
Hirsutine
Eugenol Chromanone
Pithecolobine
b-carboline
Phyllanthine
Voacangine
Vinpocetine
2.
3. 4.
5.
6.
7.
8.
9.
15. Naringin
13. 7,8-Dihydro-8hydroxypalmatine 14. Taspine
11. Matrine and oximatrine 12. Canthin-6-one
10. Capsaicin
Reserpine
Isolated compound
1.
S. no. Family
Enantia Annonaceae chlorantha Oliver Croton lechleri Euphorbiaceae Mu¨ll. Arg., Mimosa pudica Fabaceae
Increase mucin secretion
Increase mucin secretion
Mode of action
Baumeister et al. (2003) Ozaki (1989)
Reference
AIU
AIU, PLIU
EIU, AAIU, PLIU AAIU
Lewis (1989)
Increase in the production of protective endogenous nitric De souza almeida oxide et al. (2011) Histamine H2 receptor blocking activity Tan & Nyasse (2000) Reducing myeloperoxidase activity, ulcer size, and Miller et al. (2000) bacterial content of the ulcer Increase in mucosal resistance Aly & Scand (1987)
Increase mucin secretion
Stimulate the synthesis of mucus Singh (1999) Reduction of malondialdehyde, reduced glutathione levels Lemos et al. (2012) in the gastric tissue EIU, SSIU H þ , K þ and ATPase inhibition Arumugam et al. (2011) PLIU, HIU Increase mucin secretion Dharmani et al. (2005) IIU, EIU, CRIU Enhancing mucosal protection possibly by mobilization of Okoli et al. (2009) endogenous prostaglandins EIU, IIU Physico– chemical re-enforcement of the gastric mucous Koroc et al. (2009) layer EIU, AAIU, Prostaglandinmediated mechanism Nosalova et al. PLIU (1993) EIU, AIU Reduction in mucosal mucus depletion Kang et al. (1995)
IIU, EIU EIU, IIU
EIU
SIU
Animal modela
Simaba ferruginea Simaroubaceae EIU
Capsicum annuum Solanaceae L. Berberis alkaloids Berberidaceae
Rauwolfia Apocynaceae serpentina Cocculus hirsutus Menisper maceae Mentha spicata L. Lamiacea Calophyllum Clusiaceae brasiliesnse Samanea saman Leguminoseae merr Desmodium Fabaceae gangeticum Phyllanthus niruri Euphorbiaceae Linn. Voacanga Apocynaceae Africana Vinca minorL. Apocynaceae
Plant name
Table 1. Alkaloids with antiulcer activity.
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Asteraceae
EIU, IIU, PLIU Enhanced mucus production and stimulate prostaglandin- Walber et al. (2005) E2 formation Euphorbiaceae PLIU, SSIU Increased gastric and duodenal alkaline secretion Kalimuthu et al. (2010) Trigonella foenum Papilionaceae EIU Decreased gastric acid secretion Toppo et al. (2009) graecum Centella asiatica Apiaceae EIU, AAIU, Strengthening of mucosal defensive factor Shakir et al. (2007) SIU, CRIU
Senecio brasiliensis Acalypha indica
Stress induced ulcer (SIU), Indomethacin induced ulcer (IIU), Pylorus ligation induced ulcer (PLIU), Histamine induced ulcer (HIU), Ethanol-acid induced ulcer (EIU), Acetic acid induced ulcer (AAIU), Cold resistant stress induced ulcer (CRIU), Swimming stress-induced ulcer (SSIU).
a
19. Hydrocotyline
18. Trigonelline
17. Acalyphine
16. Senecionine
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Figure 2. Chemical constituents of alkaloids.
formula (C5H8)n and are classified as mono, di, tri and sesquiterpenoids depending on the number of carbon atoms. Examples of commonly important monoterpenes include terpinen-4-ol, thujone, camphor, eugenol and menthol. Diterpenes (C20) are classically considered to be resins and taxol. Terpenoids are classified according to the number of isoprene units these are monoterpene (limonene), sesquiterpene (artemisinin), diterpene (forskolin), triterpene (a-amyrin), tetraterpene (b-carotene) and polymeric terpenoids (rubber). Different terpenoids used for anti-ulcer activity are shown in Table 3 and illustrated in Figure 4. Other secondary metabolites Apart from all above-mentioned plants there are few other species which also contain potent anti-ulcer activities. These are used equally for quick and safe recovery from peptic ulcer as mentioned earlier and the important ones are mentioned in Table 4. Cause of peptic ulcer Peptic ulcer describes a condition in which there is a discontinuity in the entire thickness of gastric or duodenal mucosa that persists as a result of acid and pepsin in the gastric juice. Though they can occur at any level of the alimentary tract that is exposed to hydrochloric acid and pepsin, they can occur most commonly (98 – 99%) in either duodenal or the stomach in the ratio of 4:1 (Harsh Mohan 2009). Peptic ulcer is caused due to several causes of abnormal acid secretion, abnormal mucosal defence, reflux of bile and pancreatic juice, genetic predisposition, microbial attack, etc. Various factors involved in the formation of ulcer are shown in Figure 1.
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Figure 3. Chemical constituents of flavonoids.
Genetic predisposition: Heredity has been postulated to play a possible role in the pathogenesis of ulcer. Several rare genetic syndromes are associated with peptic ulcer, e.g. multiple endocrine neoplasias (Jamal et al. 2006). Abnormalities in the secretion of acid and pepsin: Acid – pepsin appear to be important in the pathogenesis of gastric ulcer. However, in contrast to duodenal ulcer, gastric ulcer patients generally have acid secretory rates that are normal or reduced as compared with non-ulcer patients. (Jamal et al. 2006) Abnormalities of mucosal defence: Diminished blood flow may lead to cell injury and ulceration in some patients. Gastric mucosal ischemia is believed to be a factor in the pathogenesis of acute mucosal injury and decreased bicarbonate secretion is a possible cause for diminished mucosal defence. Delayed gastric emptying: Gastric emptying has been found to be delayed in gastric ulcer. Prolonged gastric emptying cause stasis and delayed clearing of duodenal contents that have refluxed into the stomach. This in turn could damage gastric mucosa, cause gastritis and lead to ulceration. Reflux of bile and pancreatic juice: Regurgitation of duodenal contents, especially those containing bile, may induce gastric mucosal injury and subsequent gastric ulceration. Emotional stress: Emotional stress may alter factors that maintain mucosal integrity and thereby ulcers develop because of decreased mucosal defence. Cycloxygenase-1 (COX-1) is constitutively expressed in the gastrointestinal tract in large quantities and has been suggested to maintain mucosal integrity through continuous generation of prostaglandins (Halter et al. 2001).
Kaempferol rhamnoside
Sophoradin (chalconoid) Luteolin
Myricetin
Taxifolin Pinostrobin
Naringenin
2.
3.
5.
6. 7.
8.
Urticaceae
Family
Sophora flavescens
Musa sapientum Vitis vinifera and Cinnamomum verum
12. Vexibinol
13. Leucocyanidin 14. Procyanidin
Musaceae Rosaceae and Lauraceae
Fabaceae
Guttiferae
Garcinia kola Heckel
11. Kolaviron
Rutaceae Cucurbitaceae Rubiaceae
Citrus paradisi
Increased mucosal content of prostaglandin-E2 Increased mucosal content
EIU, IIU, PLIU EIU, IIU PLIU, SSIU CRIU, AIU EIU, SSIU, PLIU IIU EIU
Coelho et al. (2009) Eugine et al. (2012)
Martin et al. (1994)
Calderon-Montan˜o et al. (2011), Barnaulov et al. (1984), Sumbul et al. (2011) Lira et al. (2012), Sasajima et al. (1978), Konturek et al. (1986) Ulubelen et al. (1979), Miean and Mohamed (2001), Barnaulov et al. (1982) Hossein Hosseinzadeh et al. (2002), Clelia Akiko Hiruma-Lima et al. (2005), Calvo et al. (2007) Abdelwahab et al. (2011) Kumar et al. (2011)
Gulcin et al. (2004)
Reference
Increase in mucus secretion Protection by radical scavenging activity on the stomach surface against radical injury
Inhibits gastric acid secretion
Prabha et al. (2011) Saito et al. (1998), Souquet et al. (1996)
Yamahara et al. (1990)
Inhibition of H(þ ) K(þ )-ATPase activity Onasanwo et al. (2011)
Increase the gastric defensive factors Reducing gastric secretion
Increase in mucus secretion Increased thiobarbituric acid reactive substances levels Increase in hexosamine levels
Caricaceae and RIU, SIU, Increased prostaglandin-E2 levels Euphorbiaceae EIU, IIU
Tamarindus indica Linn. Caesalpiniaceae PLIU Boesenbergia rotunda Zingiberaceae EIU
Carica papaya and Alchornea glandulosa
Matricaria chamomilla and Brassica oleracea
Mode of action
IIU, EIU, Inhibits histamine-induced gastric acid secretion PLIU, AIU RIU, EIU, Stimulate prostaglandin-E2 formation PLIU
Animal modela
PLIU, SIU Asteraceae and RIU Brassicaceae
Myrtaceae and Syzygium aromaticum and Phyllanthus emblica Euphorbiaceae L. Sophora tonkinensis Fabaceae
Urtica dioica
Plant name
9. Orientin Wilbrandia ebracteata 10. Proanthocyanidins Ixora Coccinea
4.
Quercetin
Isolated compound
1.
S. no.
Table 2. Flavonoids with antiulcer activity.
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IIU, EIU, CRIU EIU, IIU
Asteraceae Anacardiaceae
Mikania laevigata
Mangifera indica Linn.
EIU, IIU
EIU
CRIU, PLIU EIU
Asteraceae
Lamiaceae
Silybum marianum (L.) Asteraceae Gaertn. Alhagi maurorum Boiss. Leguminosae
Scutellaria baicalensis Georgi Ligularia stenocephala
Blockade of 5-HT3 receptors
Influence para-sympathetic secretion
Inhibitory mechanism of enzymatic peroxidation Blocks histaminergic receptor
Carvalho et al. (2007), Severi et al. (2009)
Bighettia et al. (2005)
Awaad amani et al. (2006)
Lastra et al. (1992)
Preventive induction of profuse apoptosis Park et al. (2004) in the stomach Decreased volume of gastric juice Lee et al. (2010)
Stress induced ulcer (SIU), Indomethacin induced ulcer (IIU), Pylorus ligation induced ulcer (PLIU), Histamine induced ulcer (HIU), Ethanol-acid induced ulcer (EIU), Acetic acid induced ulcer (AAIU), Cold resistant stress induced ulcer (CRIU), Swimming stress-induced ulcer (SSIU), Reserpine induced ulcer (RIU), Aspirin induced ulcer (AIU).
a
18. Chrysoeriol 7-Oxylosoid 19. 7-hydroxycoumarin 20. Mangiferin
16. Caffeoylquinic acids 17. Silymarin
15. Wogonin
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Terpinen-4-ol
Betulinic acid Oleanolic acid 1,8-cineole
Tagitinin C
Epoxy-carvone
Ginsenosides RB1 or panaxosides
Populnoic acid
2.
3. 4. 5.
6.
7.
8.
9.
Anethum graveolens Xylocarpus granatum
Alpinia oxphylla Zataria multiflora Amphipterygium adstringens Standl.
12. Gedunin
13. Nootkatone
14. Carvacrol
15. 3 a-hydroxy-masticadienonic acid
Austroplenckia populnea Azadirachta Indica
Kaempferia galangal and Anethum graveolens Panax ginseng
Tithonia diversifolia
Cryptomeria japonica and Croton cajucara Benth. Melaleuca bracteata F Melaleuca bracteata F Ocimum minimum and Alpinia galangal
Zingiber officinale
Plant name
11. Limonene
10. Nimbin
Zingiberene
Isolated compound
1.
S. no.
Table 3. Terpenoids with antiulcer activity.
Anacardiaceae
Lamiaceae
Zingiber aceae
Meliaceae
Apiaceae
Meliaceae
Celastraceae
EIU
AIU
CRIU, AIU, PLIU, HIU EIU
CRIU, IIU, EIU EIU
EIU, IIU, PLIU SIU
EIU, IIU
Zingiberaceae and Apiaceae Araliaceae
EIU
IIU IIU IIU, EIU
Reference
Inhibition of the gastric acid secretion Inhibition of the gastric acid secretion Increased prostaglandins and endogenous sulfhydryls
Arrieta et al. (2003)
Mohsen et al. (2005)
Yamahara et al. (1990)
Chioma et al. (2009), Parmar (1986) Matsunaga et al. (2000), Souza et al. (2011) Inhibition of gastric acid Adesanwo et al. (2009) Inhibition of gastric acid Adesanwo et al. (2009) Mucosal gastric protection by de Sousa Maia et al. reducing gastric secretion (2005), Chudiwal et al. (2010) Stimulating the mucosal defences Sa´nchez-mendoza et al. (2011) Bruna et al. (2011) Inhibition of the gastric acid production, stimulation of mucus production Increased mucus secretion Choon Sik Jeong et al. (2003) Improvement of mucosal Andrade et al. (2006) defensive factors inhibits H þ -K þ -ATPase Chattopadhyay et al. activity (2004) Mucosal protective and Panchaxari and antisecretory effects Dandagi (2008) Inhibition of H(þ ) K(þ )-ATPase Lakshmi et al. (2010) activity
Mode of action
PLIU, IIU Inhibition of gastric secretion protects gastroduodenal mucosa EIU, AIU, Inhibition of gastric juice SSIU secretion and pepsin activity
Animal modela
Asteraceae
Myrtaceae Myrtaceae Lamiaceae and Zizibereceae
Cupressae and Euphorbiaceae
Zizibereceae
Family
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Prumnopitys andina
20. Ferruginol
Rodrı´guez et al. (2006)
Kim et al. (2005)
Kumar et al. (2011) Jain and Surana (2009)
Inhibition of Helicobacter pylori De pasquale et al. growth (1995)
Stress induced ulcer (SIU), Indomethacin induced ulcer (IIU), Pylorus ligation induced ulcer (PLIU), Histamine induced ulcer (HIU), Ethanol-acid induced ulcer (EIU), Cold resistant stress induced ulcer (CRIU), Swimming stress-induced ulcer (SSIU), Aspirin induced ulcer (AIU).
a
Xanthophyllomyces dendrorhous
IIU, EIU
PLIU, EIU Decreased gastric fluid volume EIU Increased prostaglandin E2 content Phaffiarhodozyma EIU Eliminating free radical and improving local blood circulation of the ulcer Podocarpaceae EIU Increased prostaglandin E2 content
Combretaceae
Cedrus deodara Pinaceae Gymnosporia rothiana Celast raceae
Pteleopsis suberosa
19. Astaxanthin
16. 2a,3b,19a,23,24-pentahydroxy-11-oxoolean-12-en-28-oic acid 28-O-b-dglucopyranosyl ester 17. b-himachalene 18. b amyrin
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Ehtanone
Verbascoside Plastoquinones
3-(2-hydroxyphenyl)propanoic acid Arabinogalactans type II
Methyl jasmonate
Araloside Aescin
2.
3. 4.
5.
7.
8. 9.
Tectona grandis Sargassum micracanthum Cinnamomum cassia Cochlospermum tinctorium Jasminum grandiflorum Aralia elata Aesculus hippocastanum L.
Andrographis paniculata Annona squamosa
Plant name
Araliaceae Sapindaceae
Cochlospermaceae Oleaceae
Fabaceae
Verbenaceae Sargassaceae
Annonaceae
Acanthucece
Family
HIU, PLIU CRIU, PLIU
AIU
HIU, EIU
EIU, IIU
CRIU, AIU, PLIU, HIU CRIU, PLIU EIU
CIU
Animal modela
Inhibition of gastric juice secretion induced ulcer(rats)
Inhibition of gastric juice secretion and pepsin activity Reduction in gastric fluid volume,
Inhibited the secretion of gastric acid
Inhibition of H(þ) K(þ)-ATPase activity Increase of prostaglandin-E2 levels
Basolateral and brush border membrane bound enzyme activities Inhibition of H(þ) K(þ)-ATPase activity
Mode of action
Umamaheswari et al. (2007) Lee et al. (2005) (Marhuenda et al. 1994)
Nergard et al. (2005)
Tanaka et al. (1989)
Singh et al. (2010) Mori et al. (2006)
Saranya and Geetha (2011) Yadav et al. (2011)
Reference
Stress induced ulcer (SIU), Indomethacin induced ulcer (IIU), Pylorus ligation induced ulcer (PLIU), Histamine induced ulcer (HIU), Ethanol-acid induced ulcer (EIU), Acetic acid induced ulcer (AAIU), Cold resistant stress induced ulcer (CRIU), Swimming stress-induced ulcer (SSIU), Reserpine induced ulcer (RIU), Cysteamine induced duodenal ulcer (CIU), Hypothermic restraint-stress ulcer (HIU).
a
6.
Mucin
Isolated compound
1.
S. no.
Table 4. Other secondary metabolites with antiulcer activity.
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Figure 4. Chemical constituents of terpenoids.
Calcitonin gene-related peptide (CGRP), a neuropeptide, can also prevent gastric mucosal injury (Ohno et al. 2008). Role of microbes: The bacteria Helicobacter pylori have revolutionized the approach of peptic ulcer diseases and gastritis. Almost all patients with duodenal ulcer and 80% of patients with gastric ulcers are infected with H. pylori. The organism is also associated with chronic active gastritis (stomach inflammation) and may also play a role in non-ulcer dyspepsia (the belching and bloating symptoms of indigestion). H. pylori infection has also been associated with a slightly increased risk of gastric cancer. Conclusion According to the old hypothesis, acid secretion was thought to be the sole cause of ulcer-formation and reduction in acid secretion was thought to be the major approach towards therapy. However, in the light of recent evidences this concept has changed. Now, treatment of ulcer mainly targets the potentiating of the defensive system along with lowering of acid secretion. This article glows light on cause and use of herbal medicines to treat peptic ulcer. Secondary metabolites which are obtained from ancient traditional medicinal plants, which have been used in rural or distant areas for treatment of peptic ulcer; are far away from the present world. This review article included the use of secondary metabolites such as alkaloids, flavonoids and terpenoids from various plants shows significant effect on peptic ulcer with their chemical structure, experimental models and their mode of action. The provided data may be useful for treating peptic ulcer in further research and serve the mankind. Review criteria The original research articles were searched in the Google scholar and significant database collection of records and contents of medicinal plant research from online libraries. The last decade articles were selected to prepare this review.
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Disclosure statement No potential conflict of interest was reported by the author.
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