Biotechnological aspects of plants metabolites in the treatment of ulcer: A new prospective
Abstract
Graphical abstract
Highlights
•Plant secondary metabolites in the ulcer treatment.
•Advancement of herbal plants over allopathic treatment.
•Analysis of protein-legend interactions between the secondary metabolites and virulent factors of ulcer through molecular docking.
•Categorization of herbal plants with specificity of ulcer treatment.
Ulcer is one of the most common diseases affecting throughout the world population. The allopathic treatment of ulcer adversely affects the health by causing harmful side effects. Currently, many herbal plants and secondary metabolites have been used for the ulcer treatment. In the present review, many herbal plants and their parts (root, rhizome, bark, leaves and fruits) have been listed in the table are currently being used for ulcer treatment. These metabolites are responsible for ulcer-neutralization or anti-inflammatory properties. In silico study, plant metabolites showed interaction between protodioscin (secondary metabolites of Asparagus racemosus) and interferon-γ (virulent factor of gastric ulcer) during molecular docking. All the residues of interferon-γ exhibited hydrophobic interactions with plant metabolites. These interactions helps in understanding the plant secondary metabolites vis a vis will open a new door in the research field of new drug discovery and designing for the ulcer treatment.
1Introduction
Plants and their secondary metabolites have been used as one of the important sources in the field of medicines or health related issues since ancient times. The role of medicinal plants in the health care had been already mentioned in the Indian holy books like “Vedas” [1]. Recent report of World Health Organization (WHO) has been estimated that approx 45,000 plants being practiced for the medicinal purposes across the globe [2]. Presently, around 65% of Indian population directly are dependent upon the traditional medicine for their need of primary health [3]. Secondary metabolites of these herbal plants is an alternative source broadly used in the treatment of chronic diseases [4]. Currently, traditional medicine is broadly used in the treatment of ulcer worldwide, and has been proven as one of the best strategies for the disease management of ulcer (Fig.1).
Ulcer is a discontinuity or break in a bodily membrane in the form of wound or sores that are slow healing or keep returning. It impedes the organ of which that membrane is a part from continuing its normal functions (https://en.wikipedia.org/wiki/Ulcer). It is of many forms which occur on both, inside and outside of the human body. Currently, different types of ulcer forms are recognized in medicine such as peptic ulcer, corneal ulcer, stomach ulcer, foot or leg ulcer etc.
Ulcer causing problems in digestive system and wounds appearing in the lining of digestive track in human beings are very common. The digestive track of human beings is very sensitive and the health of digestive track can be good or bad and depends on many factors. Pepsin exposed ulcers i.e., peptic Ulcers are the most common type in the gastrointestinal tract area that result from an imbalance between stomach acid-pepsin and mucosal defence barriers and more than 4 million people affected worldwide annually [5,6].
In medicine, the ulcer which occurs as mucosal lesions which penetrate the muscularis mucosae layer and form a cavity surrounded by acute and chronic inflammation is defined as peptic ulcer [7].
Peptic Ulcers can be divided into two common types according to location, i.e. gastric ulcer (in stomach) and duodenal ulcer (in duodenum). More specific classification includes
1Type I: Ulcer along the lesser curve of stomach
2Type II: Two ulcers present - one gastric, one duodenal
3Type III: Prepyloric ulcer
4Type IV: Proximal gastroesophageal ulcer
5Type V: Anywhere
Peptic ulcer disease (PUD) is an illness that affects a considerable number of people worldwide. It is produced whenever there is imbalance between the gastro-duodenal mucosal defence mechanisms i.e. ‘protective’ factor and ‘aggressive factor’ of the luminal surface of the epithelial cells, combined with superimposed injury from environmental or immunologic agents. The aggressive factors inculde Helicobacter pylori, HCl, pepsins, nonsteroidal anti-nflammatory drugs (NSAIDs), bile acids, ischemia, hypoxia, smoking and alcohol [8].
2Symptoms
Inspite of serious bleeding, big ulcer shows some common symptoms (Fig. 2) while small ulcers rarely or mayn’t cause any symptoms [9].
3Treatments
Earlier there were mainly two ways for the treatment of the peptic ulcer, the prophylactic and therapeutic types.
3.1Prophylactic mechanism (gastroprotective or cytoprotective)
In this type of treatment, defensive factors are fortified with strengthened prostaglandin synthesis and stimulated somatostatin synthesis in addition with other gastroprotective actions inhibition of gastrin secretion [[10], [11], [12]].
In addition, oxidative damage prevention of gastric mucosa (by blocking lipid peroxidation and significant decrease in superoxide dismutase along with increase in catalase activity) ([13,14]), possible participation of the NO-synthase pathway [15] and anti-inflammatory activities are several others gastroprotective effects which helps in the treatment of the peptic ulcers.
3.2Therapeutic mechanism
Therapeutic agents cure the diseases via. antisecreatory or healing activities. Antisecreatory activity has the antagonism of histaminergic and cholinergic effects on gastric secretion or proton pump inhibition mechanism while healing activity works by making ulcer to heal by local mucosal enhancement.
3.3Synthetic drugs
There is a plethora of different classes of pharmacological drugs that showed their efficacy in the treatment of peptic ulcer. Besides their novel cause, they could also destroy a person’s life by causing a general deterioration of quality of life along with creating several other life hazards. Synthetic drugs of different classes applied in the treatment with their mechanism of action (MOA) and side effects are given in Table 1.
Drug class | MOA | Medicine used | Side Effects |
---|---|---|---|
Anti-Muscarinie |
| Pirenzepine |
|
H2-receptor blockers |
| Cimetidine, Famotidine, Ranitidine |
|
Prostaglandins |
| Misoprostol |
|
Antacids |
| Sodium bicarbonate, Calcium bicarbonate |
|
Proton pump inhibitors |
| Omeprazole, Esomeprazole, Pantoprazol |
|
Mucosal protective agents |
| Sucralfate, Bismuth Subsalicylate |
|
4Plant and their products with anti-ulcer activity
Natural products exhibit their antiulcerogenic activities via. prophylactic or therapeutic or by both ways. Extracts of Saussurea lappa C.B. Clarke [16], Zizyphus oenoplia (L.) Mill. [17], Zingiber Officinale Roscoe [15], Butea frondosa (Roxb.) [18], Anacardium humile St. Hil. [10], Lasianthera Africana P. Beauv. [19], Gymnosporia rothiana [20], Coccinia grandis Linn. [21] and Zataria multiflora Boiss. [22] showed cytoprotective mechanism to treat PUDs. Extracts possessing antioxidant mechanism in the gastroprotection are Encholirium spectabile Mart. [13], Parkia platycephala Benth. [23], Glycyrrhiza glabra L. [24] and Carica papaya L. [25].
Therapeutic agents are extracts of Terminalia chebula Retz. [26], Mikania laevigata Schultz Bip. [27] and Pausinystalia macroceras (K. Schum.) Pierre ex Beille [28]. While plant extracts that perform through healing activity includes Quassia amara L. [29], Matricaria chamomilla L. [30] and D-002 (mixture of higher aliphatic primary alcohols isolated from beeswax) [31]. Another ways of wound healing mechanisms includes thick coating of the extract (like Rhizophora mangle L.) which is macroscopically adherent to the gastric mucosa, forming a physical barrier with similar properties as observed in topical wounds [32].
In addition, there are some plant extracts that exhibit both the prophylactic and therapeutic mechanisms like Mentha arvensis L. [33], Polyalthia longifolia (Sonn.) Thwaites (PL) [34], Strychnos potatorum Linn (Loganiaceae) [35], Alhagi maurorum Boiss. [36], Indigofera truxillensis Kunth [37], Syngonanthus bisulcatus (Koern) Ruhland [38], Pausinystalia macroceras (K. Schum.) Pausinystalia yohimba Pierre ex Beille [28] (Table 2).
Plant | Family | Dose applied (mg kg−1) | Mode of Action | References |
---|---|---|---|---|
Saussurealappa | Asteraceae | 200–400 | Cytoprotective effect | Sutar et al. [16] |
Zizyphusoenoplia (L.) | Rhamnaceae | 300 | Increase in prostaglandin synthesis | Jadhav and Prasanna [17] |
Zizyphus lotus (L.) | Lamiaceae | 50–200 | Cytoprotective agents | Wahida et al. [39] |
Quassiaamara (L.) | Simaroubaceae | 4.9–48.9 | Increase in gastric barrier mucus and non-protein sulfhydril groups | Garcia-Barrantes and Badilla [29] |
Cocusnucifera (L.) | Arecaceae | 100–200 | NA | Anosike and Obidoa [40] |
Encholiriumspectabile | Bromeliaceae | 100 | Protection to gastric mucosa by activation of antioxidant systems and the involvement of prostaglandins and the NO synthase pathway | de Carvalho et al. [13] |
Cissusquadrangularis (L.) | Vitaceae | 1000 | Protective effects | Shanthi et al. [41] |
Gynuraprocumbens (Merr.) | Asteraceae | 400 | Protective effects | Mahmood et al. [42] |
ZingiberOfficinale Roscoe | Zingiberaceae | 50–200 | Inhibition of ulcer index, prevented the oxidative damage of gastric mucosa by blocking lipid peroxidation, decrease in superoxide dismutase and increase in catalase activity | Arun et al. [15] |
Butea frondosa (Roxb.) | Fabaceae | 250–500 | Gastroprotective activity | Londonkar and Ranirukmini, [18] |
Parkiaplatycephala | Leguminosae | 62.5–250 | Gastroprotective activity, antioxidant effect through increase in catalase activity | Fernandes et al. [23] |
Anacardiumhumile | Anacardiaceae | 50 | Protect gastric mucosa due to increased PGE2 and mucous production | Ferreira et al. [10] |
Rhizophora mangle L. | Rhizophoraceae | 500 | Gastroprotective and antisecretory effects, in addition to increase in PGE2 levels | Sánchez et al. [32] |
Excoecariaagallocha L. | Euphorbiaceae | 62.5–125 | Decreases the acidity and increases the mucosal defense in the gastric areas | Thirunavukkarasu et al. [11] |
Erythrinaindica L. | Fabaceae | 125–500 | NA | Sachin and Archana [43] |
Glycyrrhizaglabra L | Fabaceae | 200 | Mucosal protective and antioxidant effects on the gastric mucosa | Ligha and Fawehinmi [24] |
Virolasurinamensis (Rol. ex Rottb.) Kuntze | Myristicaceae | 500 | Inhibited mucosal injury, reduced the formation of gastric lesions | Hiruma-Lima et al [44] |
Combretumleprosum Mart. &Eiche | Combretaceae | Inhibition of the gastric acid secretion and an increase of mucosal defensive factors | Nunes et al. [45] | |
Gymnosporiarothiana (Walp.) Wight &Arn. ex M.A.Lawson | Celastraceae | 250–500 | Increasing gastric mucosal defense (prostaglandin and free radical scavenging) | Jain and Surana [20] |
Spathodea falcate | Bignoniaceae | 250–500 | Increasing gastric mucosal defense (prostaglandin and free radical scavenging) | Jain and Surana [46] |
Terminalia chebula Retz. | Combretaceae | 250–500 | Inhibition of the gastric lesions due to its antisecretory | Raju et al. [26] |
Matricariachamomilla L. | Asteraceae | 400 | NA | Karbalay-Doust and Noorafshan [30] |
Morus alba L. (mulberry) | Moraaceae | 250–500 | Anti-inflammatory and antioxidant activity | Abdulla et al. [47] |
Camellia sinensis | Theaceae | 10 | Healing of gastric ulcer restoration of cellular antioxidant status | Chatterjee et al. [48] |
Centaurea bruguier | Asteraceae | 100 and 42 | Preventive activity against peptic ulcer | Khanavi et al. [49] |
Curcuma longa L. | Zingiberaceae | 20 | Antiulcerogenic, antioxidant and antiinflammatory | Mahattanadul et al. [50] |
Many researchers studied different plant species and their extracts to analyze their impact on ulcer treatments. Xiao et al. [51] during his study reported significant impact of Abrus cantoniensis ethanolic extract on the growth inhibition of Helicobacter pylori. The actual mechanism of action was not studied but they observed Abrus cantoniensis as a rich source of saponins, anthraquinones, alkaloids, flavonoids etc. The secondary metabolites present in the plants may act as anti-Helicobacter pylori substances since some metabolites analogues to the well-known anti-Helicobacter pylori compounds like cabreuvin, irisolidone, genistein and licoisoflavone [[52], [53], [54]] (Table 3).
S.No. | Botanical Name | Common name | Family | Part Used |
---|---|---|---|---|
1 | Emblica officinalis | Aamla | Euphorbiacae | Fruit &Dried bark extract |
2 | Azadirachta indica | Neem | Meliaceae | extract, Leaves |
3 | Bacopa monniera | Brahmi | Scrophulariaceae | Fresh Juice |
4 | Carica papaya | Papeeta | Caricaceae | Seeds |
5 | Ocimum sanctum | Tulsi | Labiatae | All plant parts |
6 | Morinda citrifolia | Mulberry | Rubiaceae | Fruit |
7 | Allophylus serratus | Tippani | Sapindaceae | Leaves |
8 | Centella asiatica | Gotu Kola | Apiaceae | Fresh Juice |
9 | Desmodium gangeticum | Shaparni | Leguminosae | Root Extract |
10 | Asparagus racemosus | Satavari | Liliaceae | Extract of fresh root |
11 | Zingiber officinalis | Ginger | Zingiberaceae | Powdered gingerrhizome |
12 | Musa sapientum | Banana, | Musaceae | Fruit |
13 | Aloe vera | Gritkumari | Liliaceae | Leaves |
14 | Curcuma longa | Haldi | Zingiberaceae | Rhizome |
15 | Jatropha sativa | Kalonji | Euphorbiaceae | Leaves |
16 | Vitiveria ziziinoides | Graminae | Benachar | Root |
17 | Bauhinia racemosa | Beedi leaf tree | Caesalpiniaceae | Flower buds |
18 | Capsicum annuum | Chilli | Solanaceae | Fruit |
19 | Ageratum conyzoides | Goat weed | Asteraceae | Leaves |
20 | Trianthema pentandra | Salsabuni | Aizoaceae | Whole plant |
21 | Quercus ilex | Oak | Fagaceae | Root bark |
22 | Alstonia scholaris | Saptaparn | Apocynaceae | Leaves |
23 | Punica granatum | Anaar | Lythraceae | Fruit peel |
24 | Ficus religiosa | Pipal | Moraceae | Leaves |
25 | Momordica charantia | Karela | Cucurbitaceae | Seeds |
26 | Benincasa hipsida | Pethakaddu | Cucurbitaceae | Fruits |
Saussurea lappa is also a traditional medicinal plant having anti-Helicobacter pylori properties. This plant also has a rich source of sesquiterpenes, monoterpenes, triterpenes, aromatic compounds, sterols, alkaloid [55,56]. Besides raw plant products or extracts, volatile oils of the plants also play a significant role in the inhibition of ulcer [57]. Many researchers reported different plants volatiles oil having singnificant role in anti-Helicobacter pylori like Magnolia sieboldii [58], oil-macerated garlic constituents [59] and Aristolochia paucinervis [60].
Adesanwo et al. [61] studied the antiulcerogenic effect of Melaleuca bracteata stem bark extract and showed thatthe extract significantly reduced gastric acid secretion. They also reported that the bark extract contains two important constituents’ betulinic acid and oleanolic acid, play major role in anti-ulcer effect. In another attempt, Agrawal et al. [62] studied the antiulcer activity of petroleum ether, alcohol and aqueous extracts of Smithia conferta. Phytochemical analysis of petroleum ether extract found to have steroids, alcohol extract constitute isoflavonoids, alkaloids and carbohydrates whereas in the aqueous extract significant amount of amino acids, carbohydrates and flavonoids were present. However, the aqueous and alcoholic extracts showed significant reduction in ulcer index compared to petroleum ether extract. All through in our evolution, natural products have enormous eminence in the fields of medicine and health. Natural products along being the earth friendly, they are free from any adverse effect to the human health.
5Future prospective
Plant metabolites (natural products) have been the most successful source of potential drugs since ancient period [63]. However, due to the emergence of new human diseases with the changing environment, continuous screening and validation of secondary metabolites in the form of drug identification/designing needs to be updated. Different cheminformatics approaches like target identification, active site prediction, drug likeliness properties, biological activity and molecular docking of selected phytoligands are the key features for identifying for functional aspects of any drug.
Secondary metabolites of the plants have been recognized to elicit beneficial effects in virulent factors of diseases. The raw materials and pharmaceuticals needed for the preparation of essential drugs are largely obtained from the local herbal plants [64]. The revolution of metabolic engineering and the development molecular docking algorithms approaches lead to improved molecular simulations with crucial applications in virtual high-throughput screening and drug discovery. Analysis with molecular docking of interactions between protein-ligand, become an emerging tool in drug design [65].
In case of Helicobacter pylori infected individuals, the frequencies of virulent factor IFNγ cells have been increased in the antrum, which induces development of gastric ulcers [66]. Protodioscin a secondary metabolites of Asparagus racemosus is used as medicinal compounds against several diseases [67]. The analysis by molecular docking between the virulent factor and plant metabolites showed the interaction between structural protodioscin (PubChem CID: 441891) and interferon-γ (PDB ID: 1hig), in which all residues of interferon-γ exhibited hydrophobic interactions (Fig.3). Although, the obtained binding energy (−26.96 kcal/mol) of protodioscin- interferon-γ complex revealed disruptions of interferon-γ integrity. These types of interactions between the virulent factors of ulcer and plants secondary metabolites open a new door in the field of designing and discovery of a new drug in the ulcer treatment.
Funding information
Conflict of interest
No any authors have conflict of interest.
Acknowledgements
Authors, thanks University Grants Commission and CSIR, New Delhi for fellowship in the form of JRF and SRF and also Head, Centre of Advanced Study in Botany, Banaras Hindu University for providing the laboratory facilities.
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