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Medicinal plant activity on Helicobacter pylori related diseases
Yuan-Chuen Wang, Department of Food Science and Biotechnology, National Chung Hsing University, Taichung 402, Taiwan
ORCID number: $[AuthorORCIDs]
Author contributions: Wang YC designed and performed this research, and wrote this paper.
Correspondence to: Yuan-Chuen Wang, Professor, PhD, Department of Food Science and Biotechnology, National Chung Hsing University, 250 Kuo-Kuang Rd., Taichung 402, Taiwan. firstname.lastname@example.org
Telephone: +886-4-22840385 Fax: +886-4-22854053
Received: October 24, 2013 Revised: January 17, 2014 Accepted: April 1, 2014 Published online: August 14, 2014
More than 50% of the world population is infected with Helicobacter pylori (H. pylori). The bacterium highly links to peptic ulcer diseases and duodenal ulcer, which was classified as a group I carcinogen in 1994 by the WHO. The pathogenesis of H. pylori is contributed by its virulence factors including urease, flagella, vacuolating cytotoxin A (VacA), cytotoxin-associated gene antigen (Cag A), and others. Of those virulence factors, VacA and CagA play the key roles. Infection with H. pylori vacA-positive strains can lead to vacuolation and apoptosis, whereas infection with cagA-positive strains might result in severe gastric inflammation and gastric cancer. Numerous medicinal plants have been reported for their anti-H. pylori activity, and the relevant active compounds including polyphenols, flavonoids, quinones, coumarins, terpenoids, and alkaloids have been studied. The anti-H. pylori action mechanisms, including inhibition of enzymatic (urease, DNA gyrase, dihydrofolate reductase, N-acetyltransferase, and myeloperoxidase) and adhesive activities, high redox potential, and hydrophilic/hydrophobic natures of compounds, have also been discussed in detail. H. pylori-induced gastric inflammation may progress to superficial gastritis, atrophic gastritis, and finally gastric cancer. Many natural products have anti-H. pylori-induced inflammation activity and the relevant mechanisms include suppression of nuclear factor-κB and mitogen-activated protein kinase pathway activation and inhibition of oxidative stress. Anti-H. pylori induced gastric inflammatory effects of plant products, including quercetin, apigenin, carotenoids-rich algae, tea product, garlic extract, apple peel polyphenol, and finger-root extract, have been documented. In conclusion, many medicinal plant products possess anti-H. pylori activity as well as an anti-H. pylori-induced gastric inflammatory effect. Those plant products have showed great potential as pharmaceutical candidates for H. pylori eradication and H. pylori induced related gastric disease prevention.
Core tip: Many medicinal plant products possess anti-Helicobacter pylori (H. pylori) activity as well as an anti-H. pylori induced gastric inflammatory effect. Those plant products have showed great potential as pharmaceutical candidates for H. pylori eradication and H. pylori induced related gastric disease prevention.
Citation: Wang YC. Medicinal plant activity on Helicobacter pylori related diseases. World J Gastroenterol 2014; 20(30): 10368-10382
Helicobacter pylori (H. pylori) is a spiral-shaped, Gram-negative, microaerophilic bacterium with 4 to 6 flagalla whose ecological niche is the human stomach. The bacterium was first isolated from the gastric mucosa of gastritis patients by Marshall and Warren in 1983. More than 50% of the world population is infected with H. pylori. The bacterium highly links to peptic ulcer diseases (PUD) and duodenal ulcers. Ten to fifty percent of infected individuals develop PUD, and 1%-3% of PUD patients progress to gastric cancer. The gastric cancer risk in H. pylori-infected people was 2 to 7 times of that of the uninfected. Over half of gastric cancer patients have associated H. pylori infection[3,4]. The WHO classified H. pylori as a group I carcinogen in 1994.
VIRULENCE FACTORS OF H. PYLORI
The pathogenesis of H. pylori is caused by its virulence factors shown in Table 1. Those virulence factors are responsible for H. pylori colonization [urease, flagella, and blood-group-antigen-binding adhesion (BabA)] and survival [NADPH oxidase 1 (Nox1), superoxide dismutase, catalase, phospholipase A, alcohol dehydrogenase] as well as infected tissue inflammation and even damage [Vac A, Cag A, outer inflammatory protein A (OipA), duodenal ulcer promoting A (DupA), H. pylori neutrophil activation protein (HP-NAP), Lewis x and y antigens, and lipopolysaccharide (LPS)][4-7]. Of those virulence factors, VacA and CagA play the key roles.
Table 1 Virulence factors of Helicobacter pylori[4-7].
H. pylori colonization
Buffers stomach acid, toxic effect on epithelium cells, disrupting cell tight junctions, and sheathing antigen
Active movements through mucin
H. pylori survival
Resistance to killing by phagocytes, infected-site inflammation
Resistance to killing by phagocytes
Resistance to killing by phagocytes
Digest phospholipids in cell membranes
Gastric mucosal injury
Tissue inflammation and damage
31 genes coding for type IV secretion system
Immunodominant antigen (part of cag PAI)
Induce inflammation, especially for IL-8
Induce inflammation via CagA, OipA and/or VacA
Lewis x and y antigens
Molecular mimicry, autoimmunity
Homolog of type II restriction endonuclease
H. pylori: Helicobacter pylori; BabA: Blood-group-antigen-binding adhesion; CagA: Cytotoxin associated gene antigen; DupA: Duodenal ulcer promoting A; HP-NAP: H. pylori neutrophil activation protein; IceA: Induced by contact with epithelium factor antigen; LPS: Lipopolysaccharide; Nox1: NADPH oxidase 1; OipA: Outer inflammatory protein A; Vac A: Vacuolating cytotoxin A; IL: Interleukin.
The vacA gene (3.9 kb) encodes the VacA protein and is present in all H. pylori strains. The protoxin of VacA is initially a 140 kDa protein, which undergoes both N-terminal and C-terminal cleavages to yield an N-terminal signal sequence (33 residues), a mature 88-kDa secreted toxin (p88), a small secreted peptide with unknown function, and a C-terminal autotransporter domain. The signal sequence is characterized by allelic variation with s1a, s1b, and s2, which contributes to the recognization of the inner membrane receptor of target cells. The mature p88 divides into subunits N-terminal 33 kDa (p33) and a C-terminal 55 kDa (p55) with noncovalent bonding. The N-terminal 32 hydrophobic residues of p33 play a key role in cytoplasmic membrane insertion, and p55 is essential for the toxin to bind to the plasma membrane. The p55 is also an allelic variation with m1 and m2. The strains with vacA s1/m1 alleles are more strongly associated with gastric epithelial damage and gastric ulcers[5,8-13]. As shown in Figure 1A, oligomer p88 forms anion-selective channels in the cytoplasmic membrane, which can further react with early and late endosomal compartments (EE/LE) to form anion-selective channels in the vacuole membrane. Such channels increase permeability to small organic molecules and cations Fe3+/Ni2+ which can further interact with NH4+ from H. pylori generating an osmotic force for the driving water influx and vesicle swelling, and finally leads vacuolation[5,8-12]. On the other hand, the p88/EE/LE complex could be activated by Bax and Bak, resulting in mitochondrial transmembrane potential (ΔΨm) disruption, followed by the release of cytochrome c from mitochondria to cytoplasm, activation of caspase-9 and caspase-3, and finally proceeding to apoptosis[10-12,14-17]. However, that apoptosis is inhibited by CagA (Figure 1C)[11,14,18].
Cag A, a 120 to 145 KDa protein, is encoded on the cag pathogenicity island (cag PAI) which is a 40 kb locus (containing 31 genes) that encodes for a type IV secretion system (T4SS), and is the only known effector protein to be injected into host cells[4,12,19,20]. Infection with cagA positive H. pylori strains has a high rate of severe gastric inflammation, gastritis, atrophic gastritis, and gastric adenocarcinoma[3,4,12,19-24]. Approximately 60%-70% of isolates are cagA positive. However, this rate varies geographically, to nearly 100% for East Asian countries and 60% for Western patients[4,21].
Nuclear factor-κB (NF-κB) pathway: Cag A is a multiple effector via phosphorylation independent and dependent pathways (Figure 1B and C). Once H. pylori adheres to the host’s gastric epithelial cells, CagA is injected into cytosol through T4SS to activate NF-κB-inducing kinase (NIK) and IκB kinase α/β (IKKα/β) resulting in subunit IκBα of NF-κB (trimer IκBα/p50/p60) phosphorylation and then degradation[8,12,19,25-28]. Active NF-κB (dimer p50/p60) translocates into the nucleus to transcribe the inflammatory factor genes [cyclooxygenase-2 (COX-2), intercellular adhesion molecule-1 (ICAM-1), and inducible nitric oxide synthase (iNOS)], proinflammatory cytokine genes [interleukin-6 (IL-6), interferon-γ (INF-γ), and tumor necrosis factor-α (TNF-α)], and chemokine IL-8 gene[8,19,25,27,29-31]. This is called the NF-κB pathway (Figure 1B). All of those related proteins can result in severe inflammation for infected cells. H. pylori muropeptide can also enter into cytosol through T4SS to bind with nucleotide-binding oligomerisation domain protein 1 (NOD1), and thereafter activates NF-κB[12,28,29]. On the other hand, H. pylori LPS, TNF-α, and IL-1 can enter into cell cytosol via toll-like receptor 4 (TLR4) to initiate the NF-κB pathway (Figure 1B)[19,25,27,29,30].
Mitogen-activated protein kinase pathway (MAPK): Aside from the NF-κB pathway, MAPK pathway activation is induced by CagA (Figure 1C). MAPK concerns three key kinases: C-terminal Jun-kinase (JNK), extracellular signal regulated kinase 1/2 (ERK1/2), and p38 kinase, for which the JNK pathway involves p21-activated kinase (PAK1), mitogen-activated protein (MAP) kinase kinase 4 (MKK4), and JNK; the p38 pathway involves MAP kinase 3/6 (MKK3/6) and p38; and the MEK/ERK pathway involves complex CagA/son of sevenless/growth factor receptor bound 2/rat sarcoma (CagA/Sos/Grb2/Ras), Raf, MAPK/ERK kinase 1/2 (MEK1/2), and ERK1/2. The MAPK cascades lead to transcription factor [activator protein 1 (AP-1), Elk-1/serum response element (Elk-1/SRE), Nox1, and NF-κB] activation, leading to translation of chemokine IL-8, cytokines (IL-6, TNF-α, INF-γ), and inflammatory factors (COX-2, ICAM-1, and iNOS) as well as NADPH oxidase activation[27-29,31-35].
Nox-1 pathway: The Nox-1 family consists of members gp91phox, p22phox, p47phox, p67phox, and p40phox, in which gp91phox and p22phox persist in cytosol, and p40phox, p47phox, and p67phox are located in the cell membrane[36,37]. When a host cell is attacked by H. pylori, p47phox is immediately phosphorylated (p-p47) along with p67phox, p40phox, and GTPase-Rac to translocate to the cell membrane to form a gp91phox/p22phox/p-p47phox/p67phox/p40phox/GTPase-Rac complex, an active NADPH oxidase. Active p67phox oxidizes NADPH to NADP+ and H+ which pass through gp91phox and are released to the environment; at the same time, gp91phox reduces O2 to O2-. and follows hydrogen peroxide production, resulting in oxidative stress in the H. pylori infected cells (Figure 1D)[33,35,38,39].
SHP-2/ERK pathway~CagA phosphorylation dependent: With exception to the CagA independent pathway, CagA can suffer phosphorylation by Src and Ab1 kinases, and then forms a complex with Src homology 2 (SH2)-domain containing protein tyrosine phosphatase (SHP-2) to activate ERK1/2 (Figure 1C). Both MEK/ERK and SHP-2/ERK pathways not only lead to NF-κB (Figure 1B) and Nox1 (Figure 1D) activation, but also result in cell proliferation (Figure 1C)[12,19-21,28,29].
As aforementioned, IL-8 is a chemokine which is regulated by the transcription factors NF-κB, AP-1, and Elk/SRE. IL-8 plays a key role in H. pylori infection and is an important feature in H. pylori-infected patients. As shown in Figure 1E, IL-8 infiltrates into vascular endothelial cells to activate the CD11b/CD18 dimer. The active CD11b/CD18 dimer forms a complex with neutrophil (CD11b/CD18/neutrophil), and then further binds to ICAM-1 on the vascular endothelial cell membrane (CD11b/CD18/neutrophil/ICAM-1). That tetramer (CD11b/CD18/neutrophil/ICAM-1) infiltrates into gastric epithelial cells and releases high amounts of ROS (O2-., H2O2, HOCl, OH•, and 1O2) through neutrophil NADPH oxidase, resulting in oxidative burst[27,29,33,40]. Additionally, IL-8 can activate polymorphonuclear cells and/or macrophages to produce IL-12 which further amplifies the T-cell response to H. pylori.
ANTI-H. PYLORI ACTIVITY OF MEDICINAL PLANTS
Various pharmacological regimens have been studied in the treatment of H. pylori infection. Antibiotics[41,42], proton-pump inhibitors[43,44], H2-blockers[45,46], and bismuth salts are suggested standard treatment modalities, which are typically combined in dual, triple, and quadruple therapy regimens in order to eradicate H. pylori infection[41,48]. Some problems may arise upon administration of those eradication regimens, i.e. the cost, the efficacy of antibiotics regarding the pH (for instance, amoxicillin is most active at a neutral pH and tetracycline has greater activity at a low pH) and resistance to the antibiotics[49-51]. Therefore, some patients undergoing such drug regimens experienced therapeutic failure.
Plant extracts and fractions
Numerous studies have been carried out to investigate the anti-H. pylori activity of plant extracts, partially purified fractions, natural compounds, and synthetic compounds. Anti-H. pylori activity for the medicinal plant extracts and partially purified fractions is listed in Table 2, which has those results categorized as 4 classes according to their minimum inhibitory concentration (MIC): (1) strong activity (MIC: < 10 μg/mL); (2) strong-moderate activity (MIC: 10-100 μg/mL); (3) weak-moderate activity (MIC: 100-1000 μg/mL); and (4) weak activity (MIC: >1000 μg/mL). In Table 2, 34 studies including more than 80 plants were collected. Surprisingly, only a few studies exhibited strong (2.9%, 1/34) and strong-moderate (11.8%, 4/34)[53-57] activity. Most studies revealed weak-moderate (50%, 17/34)[58-73] and weak (32.4%, 11/34)[74-81] activity against H. pylori. Notably, a few plant extracts possessed strong anti-H. pylori activity. The greatest of them was Impatiens balsamina L. (Balsaminaceae), a Taiwanese folk medicinal plant. The acetone, 95% ethanol, and ethyl acetate pod extracts showed strong anti-H. pylori activity with 1.25-2.5 μg/mL of MICs and 1.25-5.0 μg/mL of minimum bactericidal concentrations (MBCs) against multiple-antibiotic [clarithromycin (CLR), metronidazole (MTZ), and levofloxacin (LVX)] resistant H. pylori strains. Such activity exceeded that of MTZ and approximated that of amoxicillin (AMX), one of the most effective drugs used in the eradication of H. pylori infection worldwide. The Persea Americana Mill. (Lauraceae), a Mexican medicinal plant, in methanol extract also showed strong anti-H. pylori activity with < 7.5 μg/mL of MIC. Remarkable anti-H. pylori activity was reported for three Paskin indigenous medicinal plant extracts: the Acacia nilotica (L.) Delile (Fabaceae) aqueous extract, the Fagonia arabica L. (Zygophyllaceae) acetone extract, and the Casuarina equisetifolia L. (Casuarinaceae) methanol extract, all of them having 8 μg/mL of MIC. The chloroform fractions from the methanol extracts of Centaurea solstitialis ssp. Solstitialis and Centaurea solstitialis ssp. solstitialis (flowers) also exhibited significantly lower MIC (1.95 μg/mL) against H. pylori, both plants having been used as Turkish anti-ulcerogenic folk remedies. The leaf hexane fraction of Aristolochia paucinervis Pomel, a Moroccan medicinal plant, demonstrated higher inhibitory activity (MIC: 4 μg/mL) against H. pylori.
Table 2 Anti-Helicobacter pylori activity of medicinal plant extracts and fractions.
Aside from plant extracts, much literature has reported on the anti-H. pylori activity of plant compounds. Table 3 lists 28 studies including 131 compounds to address their anti-H. pylori activity in which phenolics/simple phenols/polyphenols, flavonoids, quinones, coumarins, terpenoids, alkaloids, and other compounds are involved. Some of these compounds’ chemical structures are shown in Figure 2. Notably, MICs for those compounds were much lower than those of plant extracts (Table 2), over 50% of which being lower than 10 μg/mL. Specifically, of those compounds, 5 compounds [2-methoxy-1,4-naphthoquinone (MeONQ), terpinen-4-ol, pyrrolidine, 1-methyl-2-[(Z)-8-tridecenyl]-4-(1H)-quinolone, and 1-methyl-2-[(Z)-7-tridecenyl]-4-(1H)-quinolone] of MICs or 50% MICs (MIC50) were lower than 1 μg/mL, which were similar to or lower than that of AMX.
Figure 2 Chemical structures of some anti-Helicobacter pylori compounds from medicinal plants.
Table 3 Anti-Helicobacter pylori activity of compounds from plants.
Phenolics, simple phenols, and polyphenols: Phenolic compounds are commonly distributed in plants. They are classified as phenolics, simple phenols, and polyphenols. Cinnamic acid and chlorogenic acid are the common representatives of phenolics (Figure 2). Tannin is a group of polymeric phenolic substances, which is divided into two categories based on their chemical nature: hydrolyzable and condensed tannins (Figure 2). As listed on Table 3, boropinic acid (a cinnamic acid derivative from Boronia pinnata Sm.) had the lowest MIC (1.62 μg/mL); MICs for corilagin (a hydrolyzable tannin from Geranium wilfordii) against 6 H. pylori strains were 2-4 μg/mL; ellagic acid (a hydroxydiphenic acid from Rubus ulmifolius leaves) showed anti-H. pylori activity with 2-10 μg/mL of MICs, whereas 3-farnesyl-2-hydroxybenzoic acid (a hydroxybenzoic acid prenylated derivative from Piper multiplinervium) had 3.75-12.5 μg/mL of MICs against 5 H. pylori strains.
Flavonoids: Flavonoids are widely distributed throughout the plant kingdom. The family consists of 7 members: flavones, flavanones, flavonols, flavanols, flavan-3-ols (the structural unit of condensed tannins), anthocyanidins, and chalcones with C6-C3-C6 skeleton feature (Figure 2). As indicated in Table 3, the lowest MICs of flavonoids against H. pylori peaked at quercetin 3-methyl ether (isorhamnetin) (MIC: 3.9 μg/mL), a methoxylated flavonol aglycone from Cistus laurifolius leaves; kaempferol, a flavonol from Rubus ulmifolius leaves (MBC: 6 μg/mL); and cabreuvin, an isoflavone derivative from Myroxylon peruiferum (MIC: 7.8 μg/mL).
Quinones: Quinones are aromatic rings with two ketone substitutions (Figure 2). These compounds, largely responsible for flower color, are ubiquitous in nature and highly reactive. In Table 3, MeONQ (a naphthoquinone isolated from I. balsamina L.) has the strongest anti-H. pylori action of those quinones with 0.156-0.625 μg/mL of MICs and 0.313-0.625 μg/mL of MBCs against multiple-antibiotic (CLR, MTZ, and LVX) resistant H. pylori strains. The activity was equivalent to that of AMX as well as not being influenced by pH (4-8) or heat (121 °C for 15 min) treatments. Interestingly, MeONQ abounds in the I. balsamina L. pod at the level of 4.39% (w/w). Subsequently, 2-(hydroxymethyl)anthraquinone followed, which is an anthraquinone isolated from Tabebuia impetiginosa Martius ex DC (Taheebo) with 2 μg/mL of MIC.
Coumarins: The chemical structure of coumarins are benzene fused with an α-pyrone ring (Figure 2), which are responsible for the characteristic odor of hay. Coumarins are widely found in plants. Basile et al reported that aegelinol and its derivative [benzoyl aegelinol isolated from Ferulago campestris (Apiaceae) roots] showed anti-H. pylori activity with 5-25 μg/mL of MIC. In fact, many coumarin derivatives are synthetic and are commercially sold as supplementary diet products. Jadhav et al and Kawase et al studied the anti-H. pylori activity of 23 and 24 synthetic coumarin derivatives, respectively, wherein they found those coumarin derivatives to have anti-inhibitory activity, but not particularly high (MIC: 10 to > 100 μg/mL).
Terpenoids: Terpenoids derived from terpenes containing oxygen in molecule. Isoprene is the basic structural unit of terpenes. Monoterpenes (C10H16), diterpenes (C20), triterpenes (C30), and tetraterpenes (C40) commonly occur in nature (Figure 2). Arjunglucoside I is an oleanane saponine isolated from Pteleopsis suberosa Engl. Et Diels stem bark (Combretaceae), which possesses anti-H. pylori activity (MIC: 1.9-7.8 μg/mL) against vacA/cagA positive and metronidazole-resistant strains. Trichorabdal A (a diterpene from Rabdosia trichocarpa) showed strong anti-H. pylori activity with 2-5 μg/mL of MICs. A remarkable anti-H. pylori compound, terpinen-4-ol, was isolated from Sclerocarya birrea (Anacardiaceae) with 0.004-0.06 μg/mL of MIC50, being similar to that of AMX (MIC50: 0.0003-0.06 μg/mL).
Alkaloids: Heterocyclic nitrogen compounds are called alkaloids (Figure 2). The first pharmaceutically used alkaloid was porphine from the opium poppy Papaver somniferum. 1-Methyl-2-[(Z)-8-tridecenyl]-4-(1H)-quinolone and 1-methyl-2-[(Z)-7-tridecenyl]-4-(1H)-quinolone were isolated from Evodia rutaecarpa fruits traditionally used in Chinese medicine. Both alkaloids were found to have the relatively low MIC against H. pylori (< 0.05 μg/mL), which was similar to AMX and CLR.
Mechanisms of anti-H. pylori action
As aforementioned, numerous studies have reported natural products’ anti-H. pylori activity. However, only a few papers have concerned the action mechanisms. Within this literature, the mechanisms include urease activity inhibition, anti-adhesion activity, DNA damage, protein synthesis inhibition, and oxidative stress, which are each addressed below.
Urease activity inhibition: Both Acacia nilotica and Calotropis procera extracts possessed anti-H. pylori activity possibly due to inhibition of urease activity through competitive and mixed type mechanisms, respectively, in which both Vmax and affinity (Km) were changed for the latter type. The anti-H. pylori actions of 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose from Paeonia lactiflora roots were considered to work in multiple manners. The hydrophobicity of the compound facilitates it to bind to cell membranes resulting in the loss of membrane integrity as well as inhibition of urease activity and UreB (an adhesin) expression. The inhibitory effect of resveratrol against H. pylori was possibly due to inhibition of urease activity. The action mode of mixed oregano and cranberry water-soluble extract (a commercial product) may be through urease activity inhibition and disruption of energy production by inhibition of proline dehydrogenase at the plasma membrane. In an in vivo study, both the dichloromethane fraction and the ethanolic extract of Calophyllum brasiliense stem bark decreased the number of urease-positive Wistar rats, which was confirmed by the reduction of H. pylori presence in histopathological analysis.
Anti-adhesion activity: The turmeric, borage, and fresh parsley water extracts were found to inhibit adhesion of H. pylori 11637 to the human stomach section; moreover, 33.9%-61.9% of inhibition rates for antigens Lewis a and Lewis b were observed. The Glycyrrhiza glabra root aqueous extract and polysaccharides exhibited strong anti-adhesive activity under a fluroscent microscopy of human gastric mucosa aliquots with fluorescent-labeled H. pylori. EPs 7630, a commercial product of the Pelargonium sidoides DC (Geraniaceae) root extract, showed good anti-adhesive activity in a dose-dependent manner (0.001-10 mg/mL). Plaunotol, an acyclic diterpene alcohol isolated from the leaves of the plau-noi tree in Thailand, was found to suppress adhesion of H. pylori to adenocarcinoma cells as well as inhibit IL-8 secretion in a dose-dependent manner.
Oxidative stress: MeONQ exhibited very strong bactericidal H. pylori activity. The possible mechanisms of MeONQ are due to the high redox potential of the compound. When MeONQ enters the cell membrane, it is immediately metabolized by flavoenzymes and undergoes serial redox cyclic reactions to produce a high amount of ROS (O-•, MeONQ-•, and H2O2). Those ROS further damage cellular macromolecules and may lead to H. pylori death.
Amphiphilic nature of compounds: Anti-H. pylori compound terpinen-4-ol from Sclerocarya birrea (Anacardiaceae) is a monocyclic monoterpene derivative with amphiphilic nature. The strong anti-H. pylori activity of the compound was thought to be a result of its hydrophilicity and hydrophobicity. The hydrophilicity allows this compound to diffuse through surrounding water to the bacterial cell wall, whereas the hydrophobicity lets this compound close in on and partially bind to the cytoplasmic membrane resulting in the loss of membrane integrity.
Others: Glabridin (a major flavonoid of GutGards®) exhibited anti-H. pylori activity. Additionally, GutGard® showed a potent inhibitory effect on DNA gyrase and dihydrofolate reductase with 4.40 and 3.33 mg/mL of IC50, respectively. Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a major bioactive compound of Radix et Rhizoma Rhei (a Chinese herb medicine), induced H. pylori DNA damage. Flavonoids vitexin, isovitexin, rhamnopyranosylvitexin, and isoembigenin from Piper carpunya Ruiz & Pav. showed anti-H. pylori activity. Those compounds effectively released myeloperoxidase from rat peritoneal leukocytes as well as inhibited of H+,K+-ATPase activity. N-Acetylation, a major metabolic pathway for arylamine carcinogens, is catalysed by cytosolic arylamine N-acetyltransferase. Rhein, one of the bioactive component of Dahuang, effectively inhibited N-acetyltransferase activity and H. pylori growth.
ANTI-H. PYLORI-INDUCED GASTRIC INFLAMMATION OF PLANT PRODUCTS
Once H. pylori attaches to host cells, the signal transduction is immediately initiated, and then transcription/translation of the relevant inflammatory proteins, especially for IL-8, IL-6, INF-γ, TNF-α, COX-2, and ICAM-1, through NF-κB, MAPK, MEK/ERK, SHP-2/ERK, and Nox-1 pathways (Figure 1). Those proteins can further induce immune response cascades resulting in severe H. pylori-infected gastric mucosa inflammation. As proposed in the Correa pathway, the H. pylori-induced gastric chronic inflammation can progress to superficial gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, and finally adenocarcinoma. Specifically, atrophic gastritis is a critical initiating step in the progression toward gastric cancer[22-24]. There have been many studies focusing on anti-H. pylori-induced inflammation and the relevant mechanisms, in which NF-κB and MAPK pathways were the most discussed.
Inhibition of NF-κB pathway
The H. pylori-induced NF-κB pathway is presented in Figure 1B. Many natural products were found to have anti-H. pylori induced inflammation activity through the suppression of NF-κB activation. Apigenin, one of the most common flavonoids, is widely distributed in fruits and vegetables, especially abound in parsley and celery. Apigenin treatments (9.3-74 μmol/L) significantly inhibited NF-κB activation, thus, the IκBα expression increased and inflammatory factor (COX-2, ICAM-1, ROS, IL-6, and IL-8) expressions decreased. Specifically, the ROS levels decreased partially based on the intrinsic scavenging property of apigenin. Curcumin, a natural polyphenol, presents in turmeric. Activation-induced cytidine deaminase (AID) is a downstream member of NF-κB regulated by NF-κB. Curcumin significantly suppressed NF-κB activation as well as IKK activation and IκBα degradation; and therefore inhibited AID activity in the H. pylori-infected adenocarcinoma cells. Capsaicin, a terpenoid, is an active compound of chilies and chili peppers. The compound significantly inhibited H. pylori-induced IL-8 production through inhibition of IKK and NF-κB activation in a dose- and time-dependent manner. Caffeic acid phenethyl ester (CAPE), an active compound of propolis, has been reported to have anti-inflammatory and immunomodulatory properties. CAPE inhibited H. pylori-induced NF-κB and AP-1 DNA binding activity in a dose- and time-dependent manner in H. pylori-infected AGS cells. The suppression of NF-κB (Figure 1B) and MAPK (Figure 1C) pathway activation was involved, and thus TNF-α, IL-8, and COX-2 expressions decreased. Additionally, CAPE also suppressed H. pylori-induced cell proliferation. San-Huang-Xie-Xin-Tang (SHXT), a traditional oriental medicinal formula containing Rhizoma Coptidis (Coptis chinesis Franch), Scutellariae radix (Scutellaria baicalensis Georgi), and Rhei rhizome (Rheum officinale Baill), has been used to treat gastritis, gastric bleeding, and peptic ulcers. SHXT and baicalin (an active compound of SHXT) was found to decrease IκBα phosphorylation and inflammatory factor (IL-8, COX-2, and iNOS) expressions in H. pylori-infected AGS cells, of which the transduction factor NF-κB activation was inhibited. SHXT and baicalin might exert anti-inflammatory and gastroprotective effects in H. pylori-induced gastric inflammation. Zaidi et al examined the anti-inflammatory effects of selected Pakistani medicinal plants and found that 12 plants (including Alpinia galangal) exhibited strong inhibitory activity against IL-8 secretion in H. pylori-infected AGS cells at 100 μg/mL of 70% ethanol extracts. Moreover, significant ROS suppression was demonstrated in the 6 included Achillea millefolium extracts. Notably, an in vivo study of anti-inflammatory effects of CAPE was reported by Toyoda et al. CAPE has inhibitory effects on H. pylori-induced gastritis in Mongolian gerbils through the suppression of NF-κB activation in which TNF-α, INF-γ, IL-2, IL-8, KC (IL-8 homologue), and iNOS expressions significantly decreased.
With exception to H. pylori-induced cell inflammation, paeoniflorin (a benzoic acid derivative from Paeonia lactiflora pall roots) exhibited dramatic inhibition of NF-κB activation in a time- and dose-dependent manner in human gastric carcinoma cells (SGC-7901). Moreover, the compound enhanced 5-fluorouracil-induced apoptosis of the gastric carcinoma cells.
Inhibition of MAPK pathway
β-Carotene is a well-known carotenoid and 10-20 μmol/L treatment doses significantly decreased p-38, JNK, ERK1/2 phosphorylation as well as decreased DNA binding activity of NF-κB and AP-1 in H. pylori-infected AGS cells in a dose-dependent manner. The ROS level, iNOS and COX-2 expressions also decreased. Both NF-κB (Figure 1B) and MAPK (Figure 1C) pathway activation were inhibited by β-carotene. As aforementioned, curcumin significantly inhibited NF-κB activation. Foryst-Ludwig et al reported that curcumin inhibited IκBα degradation, IKKα/β activity, and NF-κB DNA-binding activity in H. pylori-infected AGS cells. Additionally, JNK1/2, ERK1/2, and p38 phosphorylation were also remarkably suppressed by the compound. The suppressions of both NF-κB (Figure 1B) and MAPK (Figure 1C) pathway activation were demonstrated in curcumin.
IN VIVO STUDIES
There have been a few studies to discuss anti-H. pylori and anti-H. pylori induced gastric inflammation (or gastritis) activities of natural products in animals. As aforementioned, tea catechins had anti-H. pylori activity (MIC: 8-256 μg/mL) in vitro. The product was given in diet (0.5%) for 2 wk to Mongolian gerbils. The H. pylori colonization reduced by 10%-36% and gastric mucosal injury significantly decreased. Both kaempferol and tryptanthrin showed anti-H. pylori activity[66,109]. A mixture of kaempferol and tryptanthrin at 5.0 mg/bw of treatment dose was orally administered to Mongolian gerbils twice a day for 10 d. The viable counts of H. pylori in the stomach significantly decreased. Quercetin, a flavonoid, is widely present in fruits and vegetables. H. pylori-infected guinea pigs were orally given quercetin at 200 mg/kgbw per day, which significantly decreased neutrophil leukocyte infiltration, H. pylori colonization, and lipid peroxide concentration in the pyloric antrum. The carotenoid-rich acetone extract of Chlorococcum sp. (a microalgae) was orally given to H. pylori-infected BALB/c mice at 100 mg/kgbw per day. The algae meal significantly decreased H. pylori density in the stomach and INF-γ and IL-4 levels in splenocytes; the H. pylori-induced inflammation in BALB/c mice was effectively inhibited. A green tea product containing 30.7% epigallocatechin gallate, 17.0% epigallocatechin, 6.4% epicatechin gallate, 5.7% gallocatechin, 4.2% gallocatechin gallate, 4.1% epicatechin, and 1.1% catechin was given in drinking water at 500-2000 ppm doses for 6 wk to H. pylori-infected Mongolian gerbils. Gastritis and the prevalence of H. pylori in the Mongolian gerbils were significantly suppressed in a dose-dependent manner. Additionally, a garlic ethanol aqueous extract was given at 1%-4% of dosages in a diet to H. pylori-infected Mongolian gerbils. The garlic extract significantly decreased hemorrhagic spots in the glandular stomach and gastritis scores as well as decreased stomach weight, which might be useful as an agent for prevention of H. pylori-induced gastritis. In a 4-wk short-term H. pylori infection model, H. pylori-infected C57BL6/J mice were orally administered apple peel polyphenol (150 and 300 mg/kgbw per day). The treatment significantly decreased H. pylori colonization, gastritis scores, and malondialdehyde levels in the animals. The Thai medicines finger-root and turmeric rhizome with 95% ethanol extracts were given to H. pylori-infected Mongolian gerbils in a basal diet at 100 mg/kgbw per day. The finger-root extract effectively decreased mucosal/submucosal chronic and acute inflammation scores for those Mongolian gerbils. The turmeric extract only reduced chronic inflammation scores, without anti-acute inflammation effects. In 32-wk and 52-wk animal tests, apigenin treatments (30-60 mg/kgbw per day) effectively decreased H. pylori colonization, atrophic gastritis, and dysplasia/gastric cancer rates in H. pylori-infected Mongolian gerbils. Apigenin has the remarkable ability to inhibit H. pylori-induced gastric cancer progression as well as possessing potent anti-gastric cancer activity.
H. pylori infection may result in severe gastric inflammation and gastric cancer. CagA is a key virulent factor, which initiates host cells’ NF-κB, MAPK, and SHP-2/ERK pathways to transcribe and translate inflammatory factors (COX-2, ICAM-1, iNOS, ROS) and proinflammatory cytokines (IL-6, IL-8, INF-γ, TNF-α). Overproduction of those substances cause extensive infected-site inflammation and then progress to superficial gastritis, atrophic gastritis, and finally gastric cancer.
Numerous medicinal plant products including plant extracts, partial purified fractions, and isolated compounds were reported for their anti-H. pylori activity. A few of them exhibited strong anti-H. pylori activity, being almost equal to clinical antibiotics. In animals, few plant products had anti-H. pylori effects which effectively decreased H. pylori colonization in the stomach. H. pylori-induced atrophic gastritis is a critical point to progress to gastric cancer. Some plant products, including isolated compounds and plant formulas, significantly decreased such gastric inflammation and injury, and even inhibited gastric cancer progression.
H. pylori eradication with antibiotic regimens has a limitation mostly due to antibiotic resistance. Medicinal plant compounds and other natural products provide another choice or opportunity to eradicate H. pylori infection. Medicinal plant compounds may also provide effective way to reduce H. pylori-induced gastric inflammation and even gastric cancer. However, potential cytotoxicity and adverse side effects might present from those medicinal plant products. Further relevant cytotoxicity studies both in vitro and in vivo will be required. Further evaluation of pharmacokin-etics for those products in animals will be also required.
P- Reviewer: Balaban YH, Kanizaj TF, Zhu YL S- Editor: Ma YJ L- Editor: A E- Editor: Ma S
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