Plants against Helicobacter pylori to combat resistance: An ethnopharmacological review.

Worldwide, Helicobacter pylori (H. pylori) is regarded as the major etiological agent of peptic ulcer and gastric carcinoma. Claiming about 50 percent of the world population is infected with H. pylori while therapies for its eradication have failed because of many reasons including the acquired resistance against its antibiotics. Hence, the need to find new anti-H.pylori medications has become a hotspot with the urge of searching for alternative, more potent and safer inhibitors. In the recent drug technology scenario, medicinal plants are suggested as repositories for novel synthetic substances. Hitherto, is considered as ecofriendly, simple, more secure, easy, quick, and less toxic traditional treatment technique. This review is to highlight the anti-H. pylori medicinal plants, secondary metabolites and their mode of action with the aim of documenting such plants before they are effected by cultures and traditions that is expected as necessity.

Introduction

Helicobacter pylori (H. pylori) is a spiral-shaped Gram-negative bacteria colonized in the gastrointestinal tract. H. pylori infection leads to peptic ulceration, gastritis, and gastric carcinoma [1]. About 50 % of the world population is estimated to be infected by this bacterium [2]. The colonization of H. pylori is caused by its infectious agents as shown in Fig. 1 and Table 1.

Fig. 1

Virulence agents of H. pylori. IL: Interleukin; TLR4: Toll-like receptor 4; NF-κB: Nuclear factor-kappaB; NIK: NF-κB-inducing kinase; VacA: Vacuolating cytotoxin A; CagA: Cytotoxin-associated gene antigen; PAK1: p21-activated kinase; IKKα/β: IκB kinase α/β; MAPK: Mitogen-activated protein kinase; MEK1/2: MAPK/ERK kinase 1/2; INF-γ: Interferon-γ; NOD1: Nucleotide-binding oligomerisation domain protein 1; ICAM-1: Intercellular adhesion molecule-1; iNOS: Inducible nitric oxide synthase, COX-2: Cyclooxygenase-2; MKK4: MAPK kinase 4; LPS: Lipopolysaccharide; TNF-α: Tumor necrosis factor-α.

Table 1

Virulence agents of H. pylori.

Vrulence agent	H. pylori Function
Vacuolating cytotoxin A (VacA)	Induce Cyto C release
	Cytotoxicity
Cag Pathogenicity Island (CagPAI)	Induce inflammation
Cag genes (Cag E,G,I,H, L and M)	Coding for 40-kb is a major virulence factor of H. pylori.
Urease	Causing epithelium cells toxicity
	Disrupting cell tight junctions
	Buffers stomach acid
	Sheathing antigen
Duodenal ulcer promoting A (DupA)	Induce inflammation
Outer inflammatory protein A (OipA)	Induce inflammation for IL-8
H. pylori neutrophil activation protein (HP-NAP)	Activation of neutrophil
BabA	Adhesin
Flagella	Movements through mucin

Pharmacological therapies

Numerous pharmacological studies have been reported for the eradication of H. pylori. Proton-pump inhibitors, antibiotics, bismuth saltsand H2-blockers (intragastric pH control drug) are recommended standard therapies [3]. A few issues may arise upon those eradication therapies, for example, the cost, the high global prevalence and the uprising resistance to available antibiotics. Consequently, some patients undergoing many of these drug regimens experience therapeutic failure [3]. Moreover, these therapies include getting too many medications which might cause side effects that, along with significant cost regarding the treatment, promote inadequate patient compliance. It is extremely desirable to explore for alternative strategies with agents to prevent or manage H. pylori-associated gastric tumor.

The quest regarding new anti-H. pylori therapies has driven exploration in the field of therapeutic plants. Many studies have been performed on a great number of plant varieties. Natural products exhibit their own anti-H. pylori actions via different mechanisms. While therapeutic agents have either antisecretory or healing effects, prophylactic compounds produce their effect via their antioxidant and anti-inflammatory mechanisms.

Mechanisms of medicinal plants as anti-H. pylori

Many natural products have anti-H. pylori potentials. The mechanisms of such potentials include urease inhibition, DNA damage, protein synthesis inhibition, and anti-inflammatory effects. In addition to the anti-H. pylori effects due to some enzymes like dihydrofolate reductase and myeloperoxidase N-acetyltransferase.

Urease inhibition

The potent effect of resveratrol as anti-H. pylori is mainly owing to ureaseinhibition [4]. The anti- H. pylori actions of Paeonia lactiflora roots is due to the hydrophobicity of 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose which facilitates thebinding to membranes leading to the loss of membrane integrity as well as urease inhibition [5]. Both the CHCl3 fraction and EtOH extract of Calophyllum brasiliense stem bark has been reported to decrease H. pylori and urease activity in Wistar rats as confirmed by histopathology [6]. The mode of action of mixed cranberry and oregano water extract may be due to inhibition of proline dehydrogenase and urease activvity [7]. BothCalotropis procera and Acacia nilotica extracts inhibit urease activity through competitive mechanisms [8].

Oxidative stress

2-Methoxy-1,4-naphthoquinoneexhibits strong anti H. pylori action. 2-methoxy-1,4-naphthoquinone is metabolized in H. pylori membrane by flavoenzymes and produces a high amount of free radicals that may damage cellular macromolecules and may lead to H. pylori death [9].

Anti-adhesion activity

Borage, parsley, and turmeric water extracts are found to be able to decrease adhesion of H. pylori [10]. The Liquoriceroot aqueous extract and polysaccharides exhibite strong anti-adhesive activity of human gastric mucosa aliquots with fluorescent-labeled H. pylori [11]. The Pelargonium sidoides root extract display antiadhesive activity [12]. The diterpene Plaunotol, isolated from the plau-noi leaves, is also found to inhibit adhesion of H. pylori as well as inhibition of IL-8 secretion [13].

Structure activity relationship

Plantswith anti H. pylori activityconsist of various phytocompounds, such as alkaloids, flavonoids, saponins, terpenes, and polysaccharides, which responsible for antimicrobial activity (Fig. 2) are discussed within this review in Table 2.

Fig. 2

Mechanisms of action of phytocompounds against microorganisms.

Table 2

Restorative herbs having anti-H. pylori action.

Plant Names	Part and extract	Active ingredients responsible for the activity	Activity	Refs.
Aesculus hippocastanum	EtOH extract	Saponin (Aescine)	Antisecretory effect	[31]
Acacia nilotica	flower aceton extract	Not identified	Urease inhibitor	[8]
Achillea millefolium	MeOH extract of aerial parts	Not identified	Antioxidant	[45,46]
Ageratina pichinchensis	EtOH extract	3,5-diprenyl-4-hydroxyacetophenone	Maintaenence NO, PG, SH release	[47]
Ageratum conyzoides	MeOH extract of the entire plant	Not identified	Not detected	[48]
Agrimonia pilosa Ledeb.	Aqueous extract of whole plant	Not identified	Not detected	[49]
Alchornea triplinervia	MeOH and EtOAc extracts	Not identified	Antisecretory	[50,51]
			Increase PGE2
			Decrease gastric injuries
			Increase mucus
			Promote epithelial cell
Allium sativum	Oil and aqeous extract	Thiosulfinates	Interfere with cell wall	[52,53,54,55,56]
		Diallyl disulfide	Causing cell lysis and Triggering autolysis
Aloe vera	Polysachharide fraction	Lectins	Increase mucus	[57]
			Inhibit aminopyrin uptake
			Reduce TNF-α
Alpinia speciosa	EtOH extract of root	Not identified	Inhibit H.pylori	[58]
Amphipterygium adstringens.	CH2Cl2 extract	3a-hydroxymasticadienonic acid, b-sitosterol	Gastroprotective	[59]
		3-epi-oleanolic acid
Angelica sinensis	EtOH extract	Polysaccharide indomethacin	Inhibition of MPO activity	[60]
Anisomeles indica	Stem and leaves EtOH extract	Not identified	Inhibit IL-12 and TNF-α,	[58]
Annona cherimola	Stem and leaves MeOH extract	Not identified	Not detected	[61]
Anthemis altissima	Isolated compounds from arial part	Sesquiterpene lactones	Not detected	[62]
		Tatridin-A, sivasinolide, 1-epi-tatridin B, altissin, desacetyl-β-cyclopyrethrosin,
Aralia elata	Root bark	Araloside A	Gastric lesion inhibitor ulcer formation inhibitor	[33]
Arrabidaea chica	HydroEtOHic extract of leaves	Flavones and flavonols	Inhibit H. pylori	[63]
Artemisia ludoviciana	Leaves and stem aqueous extract	Artemisin	Bactericidal kinetics	[61]
			Morphological degeneration
Atractylodes ovata	EtOH extract	Sesquiterpenoid	-Inhibition of MMP-2	[64]
		Atractylenolide III	-MMP-9 expression
Bixa orellana	EtOH extract of seeds	Not identified	Not detected	[65]
Boesenbergia rotunda	EtOH extract	Flavanone	Antioxidant	[66]
		Pinostrobin	Decrease gastric motility
Bombax malabaricum	EtOH extract of root	Not identified	Not detected	[58]
Boronia pinnata	Whole shrub extract	Cinnamic acid derivative (boropinic acid)	Anti-ulcer agent	[67]
Brassica oleracea	Broccoli sprouts	Not identified	On human volunteers	[68]
Brazilian propolis	Propolis extract	3-hydroxy-2,2dimethyl-8-prenylchromane-propenoic acid	Anti-H.pylori invitro	[69]
Bridelia micrantha	Acetone and EtOAc extracts of stem bark	Not identified	Anti-inflammatory	[70,71]
Byrsonima crassa	Leaves MeOH and CHCl3 extracts	Not identified	Immunostimulatory	[72]
Byrsonima fagifolia	Leaves MeOH extract	Not identified	Gastroprotective	[73]
			Antidiarrheal
			Antibacterial Immunomodulatory
Byrsonima intermedia	Leaves MeOH extract	Not identified	Antioxidant	[74]
Calophyllum b8rasiliense	Hexane, HydroEtOH extract and Ch2Cl2 fraction of stem bark	Mixture of chromanone	Decreased urease,	[6,75]
			Reduce H. pylori in pathological analysis
Calotropis procera	Acetone and MeOH extracts of leaves and flowers	Not identified	Urease inhibitor	[8]
Camellia sinensis	MeOH and water extracts of young shoots	Catechin	Urease inhibitor	[27,76,77]
			Anti-inflammatory
Carum carvi L.	Fruit MeOH	Not identified	Not detected	[78]
Casearia sylvestris	Leaves EtOH extract	Terpenoids	Decrease ulcerative size	[79]
			Eradicate H. pylori
Chamomilla recutita	Oil extract of flowers	Catechin	Urease inhibitor	[65,80,81,82]
	70 % aqueous		Decreasegastric mucosal injury
	MeOH 96 % ethanol
Cinnamomum cassia	Bark aqueous EtOH	Not identified	Suppression of IL-8	[46]
Cinnamomum verum	Essential oils of dry bark	Cinnamaldehyde	Urease inhibitor	[83,84,85,86]
Cistus laurifolius	Flowers CHCl3 fraction	Isorhamnetin	Inhibit ulcer	[87,88]
		Kaempferol 3,7-dimethyl ether, quercetin 3,7-dimethyl ether	Eradicate H.pylori
Citrus aurantium	EtOH extract	Monoterpene	indomethacin, ischemia reperfusion	[89]
		b-Myrcene
Citrus lemon	Essential oil	Monoterpene	Mucus production	[90]
		Indomethacin	HSP-70 activation
		Limonene	Vasoactive intestinal peptide and NO release
			Maintenance of PGE2 and glutathione levels
Cocculus hirsutus	EtOH extract of leaves	Alkaloids	Anti H. pylori	[91]
Cochlospermum tinctorium	Acidified EtOH	Polysaccharide	Antioxidant	[40]
		Arabinogalactans II	Immunomodulatory
Combretum molle	Stem bark acetone extract was the best	Flavonoids	Gastroprotective	[92]
Coptis chinensis	Rhizome aqueous extract	Alkaloid	Inhibit ulcer	[93]
			Eradicate H.pylori
Croton reflexifolius	EtOH extract	Diterpenoid	Gastroprotective	[94]
		Polyalthic acid	Block sulfhydryl groups
			Inhibit NO synthase
Croton sublyratus	Leaves extract	Terpenoid (Plaunotol)	Suppress IL-8 secretion	[95]
Cuminum cyminum	EtOH extracts of seeds	Phenolic compounds	Antioxidant	[96]
Cuphea aequipetala	Leaves aqueous extract	Phenolic compounds	Reduce gastric lesions	[61]
			Inhibit ulcer
Curcuma amada	Rhizome 70 % EtOH	Curcumin	Inhibit proton potassium ATPase	[97]
Cupressus sempervirens	Essential oil	Monoterpenes	Not detected	[98]
Curcuma longa	Polyphenolic rich extract of the root	Curcumin	Chemo-preventative	[99]
Cymbopogon citratus	Essential oil	Terpenes	Inhibit COX	[98]
			Inhibit NO synthase Activate K+ATP channel and α2 receptors.
Cyrtocarpa procera	Hexane extracts from stem bark	Not identified	Gastroprotective	[59,61,100]
			Anti-inflammatory
Davilla elliptica	Leaves MeOH extract	Not identified	Anti-inflammatory Gastroprotective	[101]
Davilla nítida	Leaves MeOH extract	Not identified	Anti-inflammatory Gastroprotective	[101]
Daucus carota	Essential oil of seed	Carvacrol and nerol	Decrease pH	[102]
Derris trifoliate	Petroleum ether and stemCHCl3 extracts	Not identified	Eradicate H. Pylori	[103]
			Gastroprotective
Desmostachya bipinnata	Wholeplant	Flavonoids (4-methoxy quercetin-7-O-glucoside)	Chemopreventive agent	[104,105]
	Diethyl ether extract
Dittrichia viscosa	Aerial parts essential oil (Oxygenated fractions)	3-methoxy cuminyl isobutyrate	Antibacterial action	[81,106]
Eucalyptus torelliana	Hexane extract of leaves	Saponin and taninns	Decrease gastric acid	[107]
			Increase pH gastric juice
Eugenia caryophillus	EtOH extracts of flowers	Eugenol	Increase activity at acidic pH	[84,108]
Eugenia caryophyllata	Flowers aqueous extract	Essential oil	Anti-inflammatory	[49]
Eupatorium aschenbornianum	EtOH extract	Chromene	Antioxidant activity	[109]
		Encecanescin
Evodia rutaecarpa	Alkaloids rich extract	1-Methyl-2-[(Z)-7-tridecenyl]-4-(1 H)-quinolone	Anti-inflammatory	[110]
			Very strong Anti-H.pylori
Feijoa sellowiana	Fruit Acetone Extract	Flavone	Inhibit H+/K+ATPase activity and Increase PGE2	[111]
Ferulago campestris	Root extract	Coumarins (Aegelinol and Benzoyl aegelinol)	Not detected	[112,113,114,115]
Foeniculum vulgare	MeOH extract of the seeds	Not identified	Antioxidant	[45,46]
Garcinia achachairu	Acidified ethanol of the seeds	Polyisoprenylated benzophenone	Gastroprotective	[116]
		Guttiferone A
Geranium wilfordii	EtOH extracts and EtOAc fraction	1,2,3,6-tetra-O-galloyl-β-d-glucose and corilagin	Not detected	[117]
Geum iranicum	Aqueous fraction of the roots	Tannins	Gastroprotective	[118]
		Eugenol
Glycyrrhiza glabra	Water extract of the root	Polysaccharide	Anti-adhesive activity	[11,29]
		Flavonoids (glabridin)	Inhibit dihydrofolate reductase
			Inhibit DNA gyrase
Glycyrrhiza uralensis	MeOH extract of roots	licoricidin licoisoflavone B	Chemopreventive agents	[119,120]
		licoric
Guaiacum coulteri	Bark MeOH extract	Not identified	Antibacterial action	[61]
Hancornia speciose	Hydroalcoholic extract of the bark	Not identified	Antibacterial action	[121]
Hericium erinaceus	Hydroalcoholic extract of bark	Not identified	Antibacterial action	[122]
Hydrastis canadensis	MeOH extract of rhizome	Isoquinoline alkaloids	Inhibit bacterial efflux pumps, Inhibit of nucleic acid synthesis, Inhibite the enzyme dihydrofolate reductase	[123,124,125,126]
		Berberine
		Hydrastine
Hyptis suaveolens	EtOH extract	Diterpene, IndomethacinSuaveolol	NO, PGE2, SH compounds	[127]
Impatiens balsamina	Pod acetone, EtoAc, terpenoid fraction	2Methoxy1,4naphthoquinone	Produce ROS to damage H pylori cell membrane	[9]
		Stigmasta7,22-diene3βol
Ixeris chinensis	Boiling water,EtOH and CHCl3 extract was the active one	Not identified	Antibacterial	[128]
			Antiadhesive
			Anti-inflammatory
			Inhibit IL-8, NO, TNF-α
Jatropha isabelli	Acidified EtOH	Monoterpene	Gastroprotective	[129]
		1,4-Epoxy-ρ-menthan- 2-ol
		Sesquiterpene
		Cyperenoic acid
		Triterpene
		Acetyl aleuritolic acid
		9b,13a- Dihydroxyisabellione
		Diterpene
		Jatropholone A
		Jatropholone B Jatrophone
Juglans regia	Fruit MeOH extract	Xanthanolide	Not detected	[130]
Larrea divaricata	Branches and leaves aqueous extract	Nordihydroguaiaretic acid	Anti-inflammatory	[131]
			Gastroprotective
			Anti-gastric cancer
Lycopodium cernua	Whole plant hexane extract	The powerful compound was found in hexane fraction	Not detected	[48]
Magnoliae officinalis	Ether fraction of cortex	Magnolol	Antigastritic, antioxidant, neutralize acid, inhibit the secretion of gastric acid	[132]
Mallotus phillipinesis	70 % EtOH extract of fruit	Isorottlerin, rottlerin	Not detected	[97]
		3′-prenylrubranine, 5,7-dihydroxy-8-methyl-6-prenylflavanone
Malva sylvestris	Inflorescence and leaves EtOH Extract	Not identified	Not detected	[65]
Mangifera indica	Pet-ether and EtOH extracts of leaves	Mangiferin	Gastroprotective Antisecretory, antioxidant	[133,134]
Mentha piperita	Leaves andstem aqueous extract	Essential oil	antisecretory,antioxidant, anti-inflammatory, and antiapoptotic actions	[61]
		Menthol
Mentha sp.	EtOH extract	Monoterpene	Increase PGE2	[38,39]
		Indomethacin pyloric ligature	Antiapoptotic,Antioxidant
		Menthol	Anti-inflammatory
Morus alba	leaves EtOH extract	Steroid, Albosteroid	Antisecretory	[135,136]
		Pyloric ligature	Antioxidant
Mitrella kentii	EtOH extract	Chalcone	Antiapoptotic, antioxidant	[137]
		Desmosdumotin C	Inhibit COX-2
Musa acuminata	Crude flavonoids extract	Flavonoids	Increase mucus	[138,139]
		Leucocyanidin
Myristica fragrans	MeOH extracts of seeds and aerial parts	Not identified	Gastroprotective	[97,140]
Myroxylon peruiferum	Isolated compound	Isoflavone	Inhibit NADH oxidation	[141]
		Cabreuvin
Myrtus communis	Essential oil	Monoterpenes	Inhibit urease	[86,142]
Olea europaea	Leaves MeOH extract	Not identified	Increase gastric flora	[143]
			Reduce H. pylori
Ocimum sanctum	Fixed oil	Not identified	Inhibit lipoxygenase	[144]
			Antisecretory
			Histamine antagonistic
Origanum majorana L.	Aerial parts MeOH extract	Phenolic compounds	Enhance protective host defence	[45]
Oroxylum indicum	Crude Flavone glycosides	7-O-methylchrysin, 5-hydroxy-749-dimethoxyflavone, oroxylin A, chrysin, and baicalein	Gastroprotective	[145,[146]
Paeonia lactiflora	Root lipid fraction	Lysophosphatidic acidPaeonolbenzoic acidmethyl gallate,1,2,3,4,6-penta- O-galloyl-β -D-glucopyranose	Increase PG E2Decrease membrane integrityInhibit ureaseInhibit UreB (an adhesin)	[5,147]
Panax ginseng	Polysaccharides fraction	Galacturonic acid	Anti-adhesive	[148,149]
Papaver somniferum	Alkaloids	Porphine	Not detected	[150]
Pausinystalia yohimbe	Alkaloids	Yohimbine	Decrease ulcer	[44]
Peperomia pellucida	EtOH extract	AllylbenzeneDillapiole	Gastroprotective	[151]
Persea americana	MeOH extracts of leaf	Procyanidins	Inhibit urease	[61]
Piper carpunya	Flavonoids rich extract of the leaves	VitexinIsovitexin RhamnopyranosylvitexinIsoembigenin	ReleasemyeloperoxidaseInhibite H+,K + ATPase activity N-Acetylation	[154]
Piper multiplinervium	Hydroxybenzoic acid prenylated derivative	3-farnesyl-2-hydroxybenzoic acid	Treat stomach aches	[155]
Pistacia lentiscus	Mastic gum	Triterpenic acids	Induce blebbingCellular fragmentation Morphological abnormalities in H. pylori cells	[156,157,158,159]
Plectranthus grandis	EtOH extract	Diterpenes3b-Hydroxy-3- deoxibarbatusin Barbatusin	K+ATP channel NO, TRPV1 channels	[160]
Plumbago zeylanica	EtOAc of rhizome	NaphthoquinonePlumbagin	Bactericidal activity	[58,161]
Polygala cyparissias	EtOH extract	Xantone	Anti-ulcerGastroprotective	[162]
Polygonum tinctorium	Leaf juice	TryptanthrinKaempferol	decrease numbers of colonies in gerbils stomachs	[163]
Polygala cyparissias	EtOH extract	Sterola-Spinasterol	Reduce percentage of lesion areaReduce ulcer index	[162]
Potentilla fruticose	Aqueous extracts of aerial part	Not identified	Antibacterial action	[164]
Prunus dulcis	Polyphenol-rich extracts of skin	Protocatechuic acid	Post gastric plus duodenal digestion	[165]
Prumnopitys andina	Acidified EtOH	Diterpene, acetic acidFerruginol	PGE2 productionInhibit lipoperoxidation	[37]
Psoralea corylifolia	Seeds extract	Psoracorylifols	Antibacterial	[166]
Pteleopsis suberosa	MeOH extract of stem bark	Oleanane saponine Arjunglucoside I	AntivacA/cagA positive and metronidazole-resistant strains	[167]
Punica granatum	EtOH, MeOH, BuOH and aqueous extracts from fruit peel	Phenolic compounds	Chang hydrophobicity of H. pylori cell surface	[130,168,169]
Phyllanthus niruri	Aqueous extracts of leaves	Ellagic acidHydroxycinnamic acid	Damage H.pylori cell membrane	[103,152]
Physalis alkekengi	EtOAc extract of the aerial parts	QuercetinPhysalindicanols A kaempferol Blumenol A	AntiinflammatoryAntiulcer invivoAnalgesic	[153]
Qualea parviflora	MeOH extract of bark	TriterpenesSaponins	Maintaine GSH levels Increase SH compoundsStimulate PGE2 synthesis	[170]
Rabdosia trichocarpa	MeOH extract from entire plants	DiterpeneTrichorabdal A	Strong antibacterial action	[171]
Rhei Rhizoma	Rhizome	Emodin	Damage DNA H. Pylori	[30]
Rheum palmatum	Rhizome	Rhein	Inhibite N-acetyltransferase	[172]
Rheum rhaponticum L.	Root EtOH Extract	Not identified	Anti-inflammatory	[56]
Rosmarinus officinalis	Leaves MeOH extract	Not identified	Antiulcer, vasodilatorGastroprotective	[45]
Rubus imperialis	EtOH extract	Triterpene2b,3b-19a-Trihydroxy ursolic acid	Not detected	[173]
Rubus ulmifolius	Leaves extract Flavonoids	EllagicKampferol	Reduce gastric PHParticipate No and SH	[26]
Ruta graveolens	Aqueous EtOH extract of leaves	Polyphenols	AntioxidantAnti-inflammatoryInhibit IL-8 secretion	[46]
Salvia mirzayanii	MeOH extract of leaves	Not identified	Not detected	[174]
Sanguinaria Canadensis	MeOH extracts of rhizome	Sanguinarine, chelerythrine, two benzophenanthridine alkaloids	Anti ulcer	[123,175]
Santalum album	hydro-alcoholic extract of stem	(Z)-R-santalol (7), (Z)-β-santalol, (Z)-lanceol	Strong antiulcer	[176]
Schinus molle	EtOH extract	Flavonol, Rutin	Antioxidant	[177]
Sclerocarya birrea	Essential oil	Terpinen- 4-ol	Decrease membrane integrity	[110,178]
Senecio brasiliensis	Inflorescences	Integerrimine, retrorsine, senecionine, usaramine, and seneciphylline	Increase mucus	[42,43]
	Pyrrolizidine alkaloids		Increase PG
Simaba ferruginea	Rhizome fractions	Alkaloid	Antiulcerogenic	[41]
		Canthin-6-one	Reduce myeloperoxidase malondialdehyde
			Reduce plasma IL-8
Scleria striatinux	MeOH extract of roots	Okundoperoxide	Antibacterial	[48]
Solanum paniculatum L.	New isolated steroids saponins	diosgenin 3-O-b-d-glucopyranosyl(10 → 69)-O-b-d-glucopyranoiside.	Decrease gastric lesion	[179]
			Decrease levels of MPO in the mucosa
Sphacele chamaedryoide	EtOH extract Diterpene	Horminone, Carnosol	Gastroprotective	[180]
		Taxoquinone	Inhibit gastric lesions
Stachys setifera	MeOH extracts of leaves	Not identified	Not detected	[181]
Strychnos pseudoquina	Leaves MeOH extract	Alkaloid enriched fraction	Increase cell proliferation in gastric mucosa	[182]
Syzygium aromaticum	Flower buds	Flavonoids	Antiulcerogenic	[183,184]
		Tannins	Antisecretory
			Increase PGE
Tabebuia impetiginosa	Inner bark	(hydroxymethyl)anthraquin	Strong antibacterial	[185]
		anthraquinone-2-carboxylic
		Lapachol, plumbagin
Termitomyces eurhizus	Mushroom	Polysaccharides fraction	Stimulate mucosal regeneration and proliferation	[186]
			Restoring gastric mucus
			Increase PG E2
			Modulate COX-1 and COX-2
			Reduce TNF-α and IL-1b
Terminalia spinosa	Young branches crude extract	Not identified	Not detected	[187]
Terminalia chebula	Aqueous extracts of fruit	Chebulinic acid	Improve secretory of B runner gland	[188,189,190]
		Ethyl gallate gallic acid
Thymus vulgaris	Essential oils	Monoterpenes	Gastroprotective	[191]
			Anti-inflammatory
Tithonia diversifolia	EtOH extract	Sesquiterpene	Gastroprotective	[192]
		Indomethacin, Tagitinin C
Trachyspermum copticum	Mixture of petroleum / MeOH extract of fruit and leaves	Not identified	Antibacterial	[78,193]
Vaccinium macrocarpon	Cranberry juice	Polyphenols	Anti-adhesive	[194,195]
Vitis venefera	Grape seeds	Resveratrol	Chemopreventative	[4]
	Flavonoids
			Antioxidant
Xanthium brasilicum	Aerial parts MeOH, diethyl ether and benzene	Not identified	Antimicrobial	[78]
Zataria multiflora	Essential oils of aerial parts	Thymol, carvacrol	Enhance mucosa Cytoprotective	[83,196]
Zingiber officinalis	Root extract	6-gingesulphonic acid	Inhibit thromboxane synthetase	[45,197,198,199,200,201,202]
		6-shogaol, Arcurcumene
		Gingerols

Methanol: MeOH; Ethanol: EtOH; Butanol: BuOH; Dichloromethan: CH2Cl2; Chloroform:CHCl3; Prostaglandin: PG; Tumor necrosis factor: TNF; Interlokin: IL; Cyclooxiginase: COX; Nitric oxide: NO; sulfhydryl : SH.

Sterol

The presence of a free OH group in C-3 is necessary for the antiulcer action of triterpenoids and sterols consistently, the only structural difference between the active 3a-hydroxymasticadienonic acid (Fig. 3, 1) and the inactive masticadienonic acid (Fig. 3, 2) is the presence of an OH group and a CO group in the C-3 [14,15].

Fig. 3

Chemical structure of 3a-hydroxymasticadienonic acid (1) and masticadienonic acid (2).

Flavonoids

Flavonoids have been used in the treatment of countless diseases [[16], [17], [18], [19], [20], [21]]. Flavonoids (Fig. 4) are found to display as antisecretory and cytoprotective agents by increasing PG levels, inhibiting H. pylori, decreasing histamine, and antioxidants [22]. The structure activity relationship shows that the presence of OCH3 group in the C-5 or C-7 positions, the double bonds at C-2 and C-3 and the presence pof an intact C-ring appear to increase gastroprotection potential. On the other hand, substitution with OH or OCH3 groups at C-3, C-6, or C-8 diminish the gastroprotective action.

Fig. 4

Chemical structure of anti-H.Pylori flavonoids 1) Quercetin 2) Kampferol 3) Catchin 4) tryptanthrin 5) Apigenin 6) Glabridin 7) Emodin.

Flavonoids can kill microbs by 1) membrane disruption by apigenin, catechin, naringenin, quercetin, and rhamnetin and inhibition of nucleic acid synthesis 2) inhibit dihydrofolate reductase by epicatechin, 3) inhibithelicase by luteolin and myricetin, d) inhibitgyrase/topoisomerase by apigenin, kaempferol and quercetin, 4) inhibit bacterial virulence by quercetin and kaempferol 5) inhibit quorum sensing by epicatechin, naringenin, quercetin and kaempferol 6) inhibit fatty acid synthase and peptidoglycan synthesis by taxifolin, kaempferol, luteolin, myricetin and quercetin7) inhibit Ala–Ala dipeptide synthesis by gaiangin, kaempferol, and kaempferol-3-O-glucoside, 8) inhibitpeptidoglycan crosslinking by apigenin and quercetin. 9) inhibit refflux pumps by diadzein, genistein, epicatechin and quercetin10) inhibit NADH-cytochrome c reductase activity in the bacterial respiratory chain by chalcon11) inhibit ATP synthase by epicatchin, quercetin, quercetrin, and silymarin [23].

As shown in Fig. 4, quercetin decreases lipid peroxide and neutrophil leukocyte infiltration, in the H. pylori colonization [24]. The blend of kaempferol and tryptanthrin reduce the viability of H. pylori invivo [25,26]. Upon giving green tea product that is consisted of catechin to H. pylori-infected Mongolian gerbils, both of gastritis and the prevalence of H. pylori were significantly suppressed [27]. Besides, apigenin treatments effectively eradicated H. pylori, atrophic gastritis, and gastric cancer rates in H. pylori-infected Mongolian gerbils. Apigenin is reported to have excellent ability to inhibit H. pylori as well as possessing potent anti-gastric cancer [28]. As for Glabridin, it possesses a strong inhibitory effect on dihydrofolate reductase and DNA gyrase [29]. While emodin; a major phytocompound of Rhizoma Rhei induces H. pylori DNA damage [30].

Steroid saponin

Aescine (Fig. 5) reduces the severity of ulcers by decreasing gastric secretion [31], while Ginsenoside increases the amount of mucus [32].

Fig. 5

Chemical structure of Aescine (1) and Ginsenoside (2).

According to Lee et al. [33], the saponins display antisecretory action by inhibiting acid secretion, total acid output, and lowering the pH of gastric juice [34].

Terpenes

Nerolidol (Fig. 6) has an antiulcerogenic and cytoprotective effect by increasing mucus production via increasing the PG, improving the gastric blood flow, and increasing the secretion of gastric bicarbonate and mucus [35]. In addition, terpenoids act as antioxidants, reduce the lipid peroxidation levels, and increase the activity of antioxidant enzymes in the gastric mucosa [36,37]. Menthol is a monoterpene that increases the maintenance of SH compounds and the amount of mucus and PG production. It also possesses an antisecretory effect, in addition to antioxidant, anti-inflammatory, and antiapoptotic actions [38,39]. Oleanolic acid is a triterpene that improves healing in the ulcer model. The low toxicity and the widespread occurrence in various plants support the potential development of new antiulcer drug based on triterpenes or their derivatives [37].

Fig. 6

Chemical structure of anti-H.pylori terpens 1) Nerolidol 2) Menthol 3) Oleanolic acid.

Polysaccharides

Arabinogalactan (Fig. 7) has the ability to bind on the gastric mucosa acting as a protective layer, in addition to its antisecretory activity towards gastric juice. The mucosal protective activity of Arabinogalactan is provided by an increased mucus synthesis and free radical scavenging activity. The particular mechanisms of polysaccharides are described by their potential to bind on the surface of the gastrointestinal mucosa, thereby acting as a protective layer, in addition to their antisecretory action. Their mucosal protective potentials are provided by an increased mucus synthesis and their antioxidant activity. Pectic polysaccharides obtained by aqueous extraction represent examples of the main polysaccharides displaying gastric antiulcer action [40].

Fig. 7

chemical structure of Arabinogalactan.

Alkaloids

Canthin-6-one (Fig. 8), isolated from Simaba ferruginea rhizome has been shown to be antiulcerogenic [41], while integerrimine isolated from Senecio brasiliensis was found to increase mucus and PG levels [42,43]. Melatonin, as a hormone, has the ability to scavenge free radical and ameliorating gastric blood flow [43]. Yohimbine, isolated from Pausinystalia yohimbe, decreases ulcers [44].

Fig. 8

Chemical structure of Melatonin (1), Canthin-6-one (2), Integerrimine (3), Yohimbine (4).

Conclusion

H. pylori inhibition with antibiotic therapies has a limitation mainly owing to antibiotic resistance. Medicinal herbs provide another opportunity to inhibit H. pylori. Medicinal herbs might also provide successful approach to decrease stomach cancer. However, potential cytotoxicity and side effects might present from those herbs. Therefore, further cytotoxicity investigation will be required.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.