Review Article | Open Access
Giuseppina Mandalari, Carlo Bisignano, Santa Cirmi, Michele Navarra, "Effectiveness of Citrus Fruits on Helicobacter pylori", Evidence-Based Complementary and Alternative Medicine, vol. 2017, Article ID 8379262, 8 pages, 2017. https://doi.org/10.1155/2017/8379262
Effectiveness of Citrus Fruits on Helicobacter pylori
It is known that Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, and gastric carcinoma. Due to the increased side effects of the treatment regimens and the development of antimicrobial resistance, a number of natural compounds have been tested as potential alternatives. In this review, we will examine the current knowledge on the effect of Citrus fruits and their derivatives against H. pylori, highlighting the remaining outstanding questions on the development of novel therapeutic strategies.
Natural medicines have become increasingly popular for the treatment of certain diseases and occasionally represent the basic ingredients used in medicinal industries. A wide variety of compounds with health promoting properties have been identified in plants. Fruits and vegetables are known to contain at least several hundred different types of phenolic compounds, with identified antioxidant, anti-inflammatory, and antimicrobial properties [1–3]. The antimicrobial properties of natural compounds have gained growing attention over the last few decades: this is due to the increased antibiotic resistance to a vast number of bacterial strains. Therefore, discovering novel bioactive compounds from plant products could help eradicate a number of infectious diseases. We have previously reported the antibacterial activity of polyphenols-rich natural products, including almonds [4, 5], pistachios , Citrus plants , Vitis vinifera L. , Olea europaea L. , and Citrus bergamia essential oil  and juice . In particular, the identification of novel compounds with bactericidal rather than bacteriostatic effect has attracted a lot of interest in recent years. Emerging research areas have also evaluated the role played by polyphenols that reach the large bowel, beneficially modulating the gut microbial ecosystem by increasing the number of Bifidobacterium spp., Lactobacillus spp., and Enterococcus spp. which are known for their anti-inflammatory, immunoregulatory and cholesterol lowering properties through production of short chain fatty acids [12, 13].
In this review, we examine the current literature on the effect of Citrus fruits and their derivatives against Helicobacter pylori, a pathogen colonizing the human stomach with high morbidity rate . Due to the increasing emergence of antibiotic resistance to H. pylori strains, bioactive compounds present in medicinal plants could represent valuable sources of anti-H. pylori agents. Furthermore, we will address the socioeconomic impact of the use of natural compounds in low-income countries with high infection rates of H. pylori. Still open questions on the use of novel therapeutic drugs will be highlighted.
The term “Citrus” refers to a genus of flowering plants belonging to the Rutaceae family. A number of studies report that Citrus originated from Southeast Asia, bordered by Northeast India, Burma, and Yunnan (China) [15–17]. Since ancient times, Citrus fruits have been widely consumed as important fruit tree crops. Initially, the genus Citrus only consisted of a few species, whereas a more extensive list of hybrids and cultivars is available nowadays, mainly based on Citrus maxima, Citrus medica, and Citrus reticulata. The genera Poncirus and Fortunella are related to Citrus spp. According to UN 2007 data, Brazil, China, USA, Mexico, India, and Spain are the largest Citrus-producing countries, with commercial Citrus growing areas including southern China, the Mediterranean Basin, South Africa, Australia, USA (mainly Florida, California, Arizona, and Texas), Mexico, and parts of South America . The most known examples of Citrus fruits, which are widely used for their ornamental, culinary, and medical purposes, are represented by oranges, lemons, grapefruits, and limes. Several studies have highlighted the health promoting properties of Citrus fruits, mainly related to the high content in bioactive compounds [18–22]. Citrus fruit juices could be useful for the prevention of kidney stone formation , whereas grapefruits have been proven to lower blood pressure and interfere with calcium channel blockers . Moreover, Citrus fruit juices and their flavonoids have anti-inflammatory [18, 25, 26], antioxidant , antigenotoxic , anticancer [19, 29–32], antimicrobial [33, 34], and neuroprotective [20, 35] properties, as well as the capability to modulate the hepatic lipid metabolism .
Citrus bergamia Risso et Poiteau, also called bergamot, is a less known fruit tree mainly growing in the southern coast of Calabria region (Italy), where the particular microclimate is ideal for its cultivation . It is considered as hybrid between sour orange and lime (Citrus aurantifolia [Christm. & Panzer] Swingle) or between Citrus aurantium L. (sour orange) and Citrus limon L. Burm. f. (lemon) or a mutation of the latter . Bergamot essential oil (BEO) is the main commercial product of bergamot industry, which take part in the composition of many fragrances . Recently, BEO has been evaluated for its neuroprotective  and antiproliferative [40, 41] effects. Over the years, bergamot juice (BJ) has been considered a byproduct of BEO industry; however, within the last decade, it has gained attention by the scientific community due to its potential health effects. Indeed, very recently, its antioxidant [42, 43], anti-inflammatory [18, 44–47], anticancer [29–31, 48], and antihyperlipidemic effects [49, 50] have been reported. What is left of bergamot fruit after the extraction of BEO and its squeezing is called bergamot pastazzo to which we previously characterized the flavonoids and pectins content . The flavonoid profile of the bergamot peel consisted of common Citrus species flavanone rutinosides and neohesperidosides derived from naringenin, eriodictyol, and hesperetin. Commercial pectinolytic and cellulolytic enzymes were able to hydrolyze the flavonoid glycosides and the pectic oligosaccharides present in bergamot peel . We have also investigated the prebiotic potential of a pectic oligosaccharide-rich extract enzymatically derived from bergamot peel using pure and mixed cultures of human faecal bacteria . A prebiotic is a nondigestible food ingredient able to modulate the microbiota composition of the large bowel, by selectively stimulating the beneficial bacteria through production of short chain fatty acids . The results obtained demonstrated that bergamot oligosaccharides resulted in a high increase in the number of beneficial bacteria, such as bifidobacteria and lactobacilli, whereas the clostridial population decreased. The evaluation of the antimicrobial activity of flavonoids extracted from bergamot peel demonstrated that both the whole extract and the pure compounds neohesperidin, hesperetin (aglycone), neoeriocitrin, eriodictyol (aglycone), naringin, and naringenin (aglycone) were active against a range of Gram-negative bacteria, including Escherichia coli, Pseudomonas putida, and Salmonella enterica . Studies on the biological activities of Citrus bergamia derivatives are summarised in Table 1.
3. Helicobacter pylori Infection
Helicobacter pylori is a microaerophilic Gram-negative bacterium able to colonize the human gastric mucosa. It has been identified as group 1 carcinogen by the International Agency for Research on Cancer and it is known to be associated with chronic gastritis, peptic ulcers, atrophic gastritis, intestinal metaplasia, and lymphoma or cancer development [54, 55]. Although infection rates are similar for men and women, they progressively increase with age. Approximately 50% of the world population is infected with H. pylori, with prevalence rates ranging from 20% to more than 80% in certain countries . The estimated prevalence is 70% in developing countries, mainly in the young population, and 30%–40% in the developed countries . Although the route of transmission of H. pylori remains unclear, the faecal-oral route represents an important pathway for its spread .
Amongst the genetic determinants causing H. pylori virulence, the cytotoxin-associated gene (cagA) and the vacuolating cytotoxin gene (vacA) play a crucial role. VacA, which is present in all H. pylori strains, contains at least two virulence parts , whereas cagA, not present in every H. pylori strain, is a marker for a pathogenicity island (PAI) . In particular, cagA seems to be associated with more severe clinical outcomes and an increased risk of developing gastric cancer and peptic ulcer . Type s1/m1 strains also produce a higher level of cytotoxin activity than other genotypes. A strong association between cagA and vacA signal sequence type s1 has been reported with strains carrying s1 m1 mosaic combination being able to secrete a vacuolating cytotoxin [56, 62]. A recent investigation on the impact of H. pylori antigens to the gastric mucosal barrier demonstrated a deleterious dose-influence effect of the lipopolysaccharide (LPS) . The current treatment for H. pylori uses a combination of antimicrobial and antiacid agents . A triple therapy consisting of a proton pump inhibitor (PPI) and two antibiotics, amoxicillin (AMX) and clarithromycin (CLA), or metronidazole (MTZ) and CLA and a quadruple therapy obtained by the association of PPI, bismuth, and two antibiotics (AMX + CLA or MTZ + tetracycline (TET)) are used . Nevertheless, due to increasing antibiotic resistance, eradication rates were reduced to 70–80% over the last few years. Due to the different clinical outcomes of H. pylori infection in humans and to the increased number of side effects to common treatments, more effort is needed to find novel natural or synthetic anti-H. pylori agents. The high infection rate of H. pylori in low-income countries, together with the poor management in the application of antibiotics, has increased the need for finding novel anti-H. pylori agents from medicinal plants. As a result, several naturally occurring substances have been investigated as potential alternatives for the treatment of H. pylori infection [65–68]. For instance, we have recently demonstrated that polyphenolic fractions from almond skin were active against standard strains and clinical isolates of H. pylori . A recent investigation reported the potential use of several medicinal herbs for the treatment of H. pylori and its complications . Clinical trials are therefore warranted to test the efficacy of novel natural drugs against H. pylori infection.
4. Effect of Citrus Fruits and Their Derivatives against Helicobacter pylori
It is well established that diet plays a crucial role in gastric carcinogenesis and Citrus intake has been associated with a lower risk of stomach cancer [70, 71]. Out of approximately 870,000 noncardia gastric cancer cases, 74.7% have been attributed to H. pylori infection . Therefore, a relevant number of studies have focused on the potential of Citrus fruits and their derivatives against H. pylori both in vitro and in vivo.
We have recently investigated the effect of bergamot juice against H. pylori in vitro and the potential therapeutic combination between bergamot juice and the antibiotics AMX, CLA, and MTZ . We used two reference American Type Culture Collection strains of H. pylori (ATCC 43504 and ATCC 49503) and thirty-two clinical isolates recovered from gastric biopsy samples of dyspeptic adults undergoing digestive endoscopy. The 2.5% (v/v) concentration of BJ inhibited the growth of the clinical isolates tested by 50%, while 5% of BJ reduced H. pylori viability to 90%. Furthermore, concentration dependent killing was observed with BJ against all the tested strains. A >3log10 difference in colony-forming unit (CFU) between BJ 1.25% and BJ 20.0% with H. pylori ATCC 49503 was achieved after 2 h, whereas complete killing was achieved with BJ (10% and 20%) after 8 h and with BJ (5%) after 24 h. BJ gave less killing against H. pylori ATCC 43504, with a complete bacterial killing after 6 h exposure (20% BJ). This outcome could be explained by the increased antibiotic resistance of H. pylori ATCC 43504 compared to H. pylori ATCC 49503 . In the combination assays, the association of BJ with the reference antibiotics determined a reduction of >6log10 for H. pylori ATCC 49503 after 8 h and for H. pylori ATCC 43504 after 24 h exposure to BJ. The association of BJ with the three reference antibiotics was more effective against H. pylori ATCC 49503 than H. pylori ATCC 43504. The most effective combination was BJ and CLA against the clinical isolate HP6 and HP61, with more rapid bacterial killing achieved with the cagA-positive strain (HP6).
This data confirmed the combination between BJ and the three reference antibiotics AMX, CLA, and MTZ had a synergistic effect against ATCC and clinical isolates of H. pylori. BJ was effective against H. pylori strains, both alone or in combination with antibiotics, and could therefore be used as novel strategy for the treatment of antibiotic resistance. Although the exact mechanism of action is not known, we believe that the synergistic effect may be due to the initial damage of the microbial lipid membrane by the plant compound, which would increase the permeability of the bacteria to the antibiotic.
Other authors have also reported on the activity of Citrus fruits and derivatives against H. pylori: two extracts (hexane and acetone) obtained from the leaves of Citrus unshiu, Citrus sinensis, Citrus paradisi, and Laurus nobilis demonstrated antimicrobial activity in vitro against a clinical isolate of H. pylori, with zone of inhibition diameters ranging within 0–30 mm and minimal inhibitory concentration (MIC) values of 1 : 512–1 : 4096 dilutions . The antibacterial action of 30 Chinese herbal medicines which have been frequently used to treat gastritis-like disorders was tested against a standard and 5 clinical isolates of H. pylori: Citrus reticulata had MIC values close to 60 μg/mL .
Rozza et al.  have reported on the gastroprotective mechanisms of Citrus lemon essential oil and its major compounds limonene and β-pinene and their activity in vitro against H. pylori ATCC 43504: results showed a gastroprotective effect of Citrus lemon and limonene with MIC values of 125 and 75 μg/mL, respectively. The role of β-myrcene, a minor constituent of essential oil from Citrus aurantium, in preventing peptic ulcer disease has been evaluated: results showed β-mircene was an effective inhibitor of gastric and duodenal ulcers through an increase in the levels of gastric mucosa defence factors . Hesperetin-7-O-glucoside, produced by fungal enzymatic conversion of Citrus hesperidin, was active in vitro against H. pylori, also inhibiting human intestinal maltase and HMG-CoA reductase . Other biologically active derivatives from Citrus fruits, such as 4′-geranyloxyferulic acid and boropinic acid, as well as sudachitin and 3′-demethoxysudachitin, were found active against H. pylori in vitro [78, 79].
In vivo studies on the effect of auraptene on H. pylori colonization of the gastric mucosa showed that a dietary supplementation with 50 ppm of auraptene suppressed H. pylori colonization, although it did not reduce gastric inflammation . The attenuation of gastritis was obtained by a reduction of H. pylori colonization, expression of CD74, and production of proinflammatory mediators in mice [81, 82]. The same authors identified bergamottin as one of the best candidates for the treatment of H. pylori infection .
A number of studies have investigated the effect of plant extracts against urease activity [84, 85]. It is believed that the urease secreted by H. pylori is a crucial enzyme able to protect the bacteria within the acidic environment of the human stomach. The Iranian Citrus aurantifolia and Citrus aurantium extracts revealed a strong urease inhibitory activity, with IC50 values of 432 and 465 μg/mL [84, 85].
Even though the data presented indicate that Citrus fruits and their bioactive compounds could represent appropriate sources for the development of novel effective compounds against H. pylori, additional in vivo toxicological evaluations are warranted. Intervention studies should also take into account the fact that the pharmaceutical doses supporting a protective effect may derive from a synergistic action of the numerous bioactive compounds present in a plant extract. Tables 2 and 3 summarised the anti-H. pylori activity of Citrus fruits derivatives and their compounds.
The renewed interest in exploring natural sources of alternative anti-H. pylori agents has been forced by the increased side effects to common treatments and the spread of antibiotic resistance. The use of plant extracts could help control H. pylori infection in low-income countries, where the rate of infection is particularly high. However, more clinical investigations evaluating the toxicity, chemical or physical stability, and bioavailability of plant bioactives are warranted. Several studies have evaluated the effectiveness of Citrus fruits derivatives and their bioactive compounds against H. pylori, gastric carcinoma, and urease activity, suggesting that, either alone or in combination with antibiotics, they could represent useful sources to help eradicate H. pylori and avoid gastric ulcer relapse.
|BEO:||Bergamot essential oil|
|vacA:||Vacuolating cytotoxin gene|
|PPI:||Proton pump inhibitor|
|MIC:||Minimal inhibitory concentration|
|IC50:||Half maximal inhibitory concentration.|
Conflicts of Interest
The authors declare that there are no conflict of interests regarding the publication of this paper.
Giuseppina Mandalari performed the literature review and wrote the manuscript; Carlo Bisignano, Santa Cirmi and Michele Navarra assisted in the literature review and manuscript preparation. All authors read and approved the final manuscript.
This research received no specific grant.
This review has been written within the framework of the project “MEPRA” (PO FESR Sicilia 2007/2013, Linea d’Intervento 126.96.36.199, CUP G73F11000050004) and the project “ABSIB” (PSR Calabria 2007/2013 misura 124) to MN. We also thank the Consorzio Interuniversitario “Istituto Nazionale Biostrutture e Biosistemi” (INBB).
- B. H. Havsteen, “The biochemistry and medical significance of the flavonoids,” Pharmacology and Therapeutics, vol. 96, no. 2-3, pp. 67–202, 2002.
- E. Tripoli, M. La Guardia, S. Giammanco, D. Di Majo, and M. Giammanco, “Citrus flavonoids: molecular structure, biological activity and nutritional properties: a review,” Food Chemistry, vol. 104, no. 2, pp. 466–479, 2007.
- S. Micali, G. Isgro, G. Bianchi, N. Miceli, G. Calapai, and M. Navarra, “Cranberry and recurrent cystitis: more than marketing?” Critical Reviews in Food Science and Nutrition, vol. 54, no. 8, pp. 1063–1075, 2014.
- C. Bisignano, A. Filocamo, E. La Camera, S. Zummo, M. T. Fera, and G. Mandalari, “Antibacterial activities of almond skins on cagA-positive and-negative clinical isolates of Helicobacter pylori,” BMC Microbiology, vol. 13, article 103, 2013.
- G. Mandalari, C. Bisignano, M. D'Arrigo et al., “Antimicrobial potential of polyphenols extracted from almond skins,” Letters in Applied Microbiology, vol. 51, no. 1, pp. 83–89, 2010.
- C. Bisignano, A. Filocamo, R. M. Faulks, and G. Mandalari, “In vitro antimicrobial activity of pistachio (Pistacia vera L.) polyphenols,” FEMS Microbiology Letters, vol. 341, no. 1, pp. 62–67, 2013.
- G. Mandalari, R. N. Bennett, G. Bisignano et al., “Antimicrobial activity of flavonoids extracted from bergamot (Citrus bergamia Risso) peel, a byproduct of the essential oil industry,” Journal of Applied Microbiology, vol. 103, no. 6, pp. 2056–2064, 2007.
- A. Filocamo, C. Bisignano, G. Mandalari, and M. Navarra, “In vitro antimicrobial activity and effect on biofilm production of a white grape juice (Vitis vinifera) extract,” Evidence-Based Complementary and Alternative Medicine, vol. 2015, Article ID 856243, 5 pages, 2015.
- C. Bisignano, A. Filocamo, G. Ginestra et al., “3,4-DHPEA-EA from Olea Europaea L. is effective against standard and clinical isolates of Staphylococcus sp,” Annals of Clinical Microbiology and Antimicrobials, vol. 13, no. 1, article no. 24, 2014.
- P. M. Furneri, L. Mondello, G. Mandalari et al., “In vitro antimycoplasmal activity of citrus bergamia essential oil and its major components,” European Journal of Medicinal Chemistry, vol. 52, pp. 66–69, 2012.
- A. Filocamo, C. Bisignano, N. Ferlazzo, S. Cirmi, G. Mandalari, and M. Navarra, “In vitro effect of bergamot (Citrus bergamia) juice against cagA-positive and-negative clinical isolates of Helicobacter pylori,” BMC Complementary and Alternative Medicine, vol. 15, no. 1, article 256, 2015.
- I. Martínez, G. Wallace, C. Zhang et al., “Diet-induced metabolic improvements in a hamster model of hypercholesterolemia are strongly linked to alterations of the gut microbiota,” Applied and Environmental Microbiology, vol. 75, no. 12, pp. 4175–4184, 2009.
- E. A. Trautwein, D. Rieckhoff, and H. F. Erbersdobler, “Dietary inulin lowers plasma cholesterol and triacylglycerol and alters biliary bile acid profile in hamsters,” Journal of Nutrition, vol. 128, no. 11, pp. 1937–1943, 1998.
- R. N. Ndip, A. E. Malange, J. F. T. Akoachere, W. G. MacKay, V. P. K. Titanji, and L. T. Weaver, “Helicobacter pylori antigens in the faeces of asymptomatic children in the Buea and Limbe health districts of Cameroon: a pilot study,” Tropical Medicine and International Health, vol. 9, no. 9, pp. 1036–1040, 2004.
- F. G. Gmitter and X. Hu, “The possible role of Yunnan, China, in the origin of contemporary citrus species (rutaceae),” Economic Botany, vol. 44, no. 2, pp. 267–277, 1990.
- R. W. Scora, “On the history and origin of citrus,” Bulletin of the Torrey Botanical Club, vol. 102, no. 6, pp. 369–375, 1975.
- “Market information in the commodities area: citrus fruits,” United Nations Conference on Trade and Development, 2007.
- N. Ferlazzo, S. Cirmi, G. Calapai, E. Ventura-Spagnolo, S. Gangemi, and M. Navarra, “Anti-inflammatory activity of Citrus bergamia derivatives: where do we stand?” Molecules, vol. 21, no. 10, p. 1273, 2016.
- S. Cirmi, N. Ferlazzo, G. E. Lombardo et al., “Chemopreventive agents and inhibitors of cancer hallmarks: may Citrus offer new perspectives?” Nutrients, vol. 8, no. 11, article 698, 2016.
- S. Cirmi, N. Ferlazzo, G. Lombardo et al., “Neurodegenerative diseases: might Citrus flavonoids play a protective role?” Molecules, vol. 21, no. 10, p. 1312, 2016.
- X. M. Lv, S. Y. Zhao, Z. C. Ning et al., “Citrus fruits as a treasure trove of active natural metabolites that potentially provide benefits for human health,” Chemistry Central Journal, vol. 9, article 68, 2015.
- D. A. Hyson, “A review and critical analysis of the scientific literature related to 100% fruit juice and human health,” Advances in Nutrition, vol. 6, no. 1, pp. 37–51, 2015.
- C. Y. C. Pak, “Medical management of urinary stone disease,” Nephron: Clinical Practice, vol. 98, no. 2, pp. c49–c53, 2004.
- D. A. Sica, “Interaction of grapefruit juice and calcium channel blockers,” American Journal of Hypertension, vol. 19, no. 7, pp. 768–773, 2006.
- R. C. L. A. Coelho, H. H. M. Hermsdorff, and J. Bressan, “Anti-inflammatory properties of orange juice: possible favorable molecular and metabolic effects,” Plant Foods for Human Nutrition, vol. 68, no. 1, pp. 1–10, 2013.
- R. Fusco, S. Cirmi, E. Gugliandolo, R. Di Paola, S. Cuzzocrea, and M. Navarra, “A flavonoid-rich extract of orange juice reduced oxidative stress in an experimental model of inflammatory bowel disease,” Journal of Functional Foods, vol. 30, pp. 168–178, 2017.
- A. Marino, I. Paterniti, M. Cordaro et al., “Role of natural antioxidants and potential use of bergamot in treating rheumatoid arthritis,” PharmaNutrition, vol. 3, no. 2, pp. 53–59, 2015.
- I. Álvarez-González, E. Madrigal-Bujaidar, and V. Y. Sánchez-García, “Inhibitory effect of grapefruit juice on the genotoxic damage induced by ifosfamide in mouse,” Plant Foods for Human Nutrition, vol. 65, no. 4, pp. 369–373, 2010.
- S. Delle Monache, P. Sanità, E. Trapasso et al., “Mechanisms underlying the anti-tumoral effects of Citrus bergamia juice,” PLoS ONE, vol. 8, no. 4, Article ID e61484, 2013.
- M. Navarra, M. R. Ursino, N. Ferlazzo, M. Russo, U. Schumacher, and U. Valentiner, “Effect of Citrus bergamia juice on human neuroblastoma cells in vitro and in metastatic xenograft models,” Fitoterapia, vol. 95, pp. 83–92, 2014.
- N. Ferlazzo, S. Cirmi, M. Russo et al., “NF-κB mediates the antiproliferative and proapoptotic effects of bergamot juice in HepG2 cells,” Life Sciences, vol. 146, pp. 81–91, 2016.
- M. Celano, V. Maggisano, R. F. De Rose et al., “Flavonoid fraction of citrus reticulata juice reduces proliferation and migration of anaplastic thyroid carcinoma cells,” Nutrition and Cancer, vol. 67, no. 7, pp. 1183–1190, 2015.
- R. Costa, C. Bisignano, A. Filocamo, E. Grasso, F. Occhiuto, and F. Spadaro, “Antimicrobial activity and chemical composition of Citrus aurantifolia (Christm.) Swingle essential oil from Italian organic crops,” Journal of Essential Oil Research, vol. 26, no. 6, pp. 400–408, 2014.
- S. Cirmi, C. Bisignano, G. Mandalari, and M. Navarra, “Anti-infective potential of Citrus bergamia Risso et Poiteau (bergamot) derivatives: a systematic review,” Phytotherapy Research, vol. 30, no. 9, pp. 1404–1411, 2016.
- R. Citraro, M. Navarra, A. Leo et al., “The anticonvulsant activity of a flavonoid-rich extract from orange juice involves both NMDA and GABA-benzodiazepine receptor complexes,” Molecules, vol. 21, no. 9, article 1261, 2016.
- J.-Y. Cha, Y.-S. Cho, I. Kim, T. Anno, S. M. Rahman, and T. Yanagita, “Effect of hesperetin, a citrus flavonoid, on the liver triacylglycerol content and phosphatidate phosphohydrolase activity in orotic acid-fed rats,” Plant Foods for Human Nutrition, vol. 56, no. 4, pp. 349–358, 2001.
- M. Navarra, C. Mannucci, M. Delbò, and G. Calapai, “Citrus bergamia essential oil: from basic research to clinical application,” Frontiers in Pharmacology, vol. 6, article 36, 2015.
- R. Costa, P. Dugo, M. Navarra, V. Raymo, G. Dugo, and L. Mondello, “Study on the chemical composition variability of some processed bergamot (Citrus bergamia) essential oils,” Flavour and Fragrance Journal, vol. 25, no. 1, pp. 4–12, 2010.
- M. T. Corasaniti, J. Maiuolo, S. Maida et al., “Cell signaling pathways in the mechanisms of neuroprotection afforded by bergamot essential oil against NMDA-induced cell death in vitro,” British Journal of Pharmacology, vol. 151, no. 4, pp. 518–529, 2007.
- C. Celia, E. Trapasso, M. Locatelli et al., “Anticancer activity of liposomal bergamot essential oil (BEO) on human neuroblastoma cells,” Colloids and Surfaces B: Biointerfaces, vol. 112, pp. 548–553, 2013.
- M. Navarra, N. Ferlazzo, S. Cirmi et al., “Effects of bergamot essential oil and its extractive fractions on SH-SY5Y human neuroblastoma cell growth,” Journal of Pharmacy and Pharmacology, vol. 67, no. 8, pp. 1042–1053, 2015.
- N. Ferlazzo, G. Visalli, A. Smeriglio et al., “Flavonoid fraction of orange and bergamot juices protect human lung epithelial cells from hydrogen peroxide-induced oxidative stress,” Evidence-Based Complementary and Alternative Medicine, vol. 2015, Article ID 957031, 14 pages, 2015.
- N. Ferlazzo, G. Visalli, S. Cirmi et al., “Natural iron chelators: protective role in A549 cells of flavonoids-rich extracts of Citrus juices in Fe3+-induced oxidative stress,” Environmental Toxicology and Pharmacology, vol. 43, pp. 248–256, 2016.
- R. Risitano, M. Currò, S. Cirmi et al., “Flavonoid fraction of bergamot juice reduces LPS-induced inflammatory response through SIRT1-mediated NF-κB inhibition in THP-1 monocytes,” PLoS ONE, vol. 9, no. 9, Article ID e107431, 2014.
- D. Impellizzeri, G. Bruschetta, R. Di Paola et al., “The anti-inflammatory and antioxidant effects of bergamot juice extract (BJe) in an experimental model of inflammatory bowel disease,” Clinical Nutrition, vol. 34, no. 6, pp. 1146–1154, 2015.
- D. Impellizzeri, M. Cordaro, M. Campolo et al., “Anti-inflammatory and antioxidant effects of flavonoid-rich fraction of bergamot juice (BJe) in a mouse model of intestinal ischemia/reperfusion injury,” Frontiers in Pharmacology, vol. 7, article 203, 2016.
- M. Currò, R. Risitano, N. Ferlazzo et al., “Citrus bergamia juice extract attenuates β-amyloid-induced pro-inflammatory activation of THP-1 cells through MAPK and AP-1 pathways,” Scientific Reports, vol. 6, Article ID 20809, 2016.
- G. Visalli, N. Ferlazzo, S. Cirmi et al., “Bergamot juice extract inhibits proliferation by inducing apoptosis in human colon cancer cells,” Anti-cancer agents in medicinal chemistry, vol. 14, no. 10, pp. 1402–1413, 2014.
- V. Mollace, I. Sacco, E. Janda et al., “Hypolipemic and hypoglycaemic activity of bergamot polyphenols: from animal models to human studies,” Fitoterapia, vol. 82, no. 3, pp. 309–316, 2011.
- P. P. Toth, A. M. Patti, D. Nikolic et al., “Bergamot reduces plasma lipids, atherogenic small dense LDL, and subclinical atherosclerosis in subjects with moderate hypercholesterolemia: A 6 Months Prospective Study,” Frontiers in Pharmacology, vol. 6, article 299, 2016.
- G. Mandalari, R. N. Bennett, A. R. Kirby et al., “Enzymatic hydrolysis of flavonoids and pectic oligosaccharides from bergamot (Citrus bergamia Risso) peel,” Journal of Agricultural and Food Chemistry, vol. 54, no. 21, pp. 8307–8313, 2006.
- G. Mandalari, C. Nueno Palop, K. Tuohy et al., “In vitro evaluation of the prebiotic activity of a pectic oligosaccharide-rich extract enzymatically derived from bergamot peel,” Applied Microbiology and Biotechnology, vol. 73, no. 5, pp. 1173–1179, 2007.
- G. R. Gibson and M. B. Roberfroid, “Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics,” Journal of Nutrition, vol. 125, no. 6, pp. 1401–1412, 1995.
- A. Covacci, J. L. Telford, G. Del Giudice, J. Parsonnet, and R. Rappuoli, “Helicobacter pylori virulence and genetic geography,” Science, vol. 284, no. 5418, pp. 1328–1333, 1999.
- H. Momtaz, N. Souod, and H. Dabiri, “Comparison of the virulence factors of Helicobacter pylori isolated in stomach and saliva in Iran,” The American Journal of the Medical Sciences, vol. 340, no. 5, pp. 345–349, 2010.
- M. Minami, T. Ando, S.-N. Hashikawa et al., “Effect of glycine on Helicobacter pylori in vitro,” Antimicrobial Agents and Chemotherapy, vol. 48, no. 10, pp. 3782–3788, 2004.
- R. H. Hunt, S. D. Xiao, F. Megraud et al., “Helicobacter pylori in developing countries. World gastroenterology organisation global guideline,” Journal of Gastrointestinal and Liver Diseases, vol. 20, no. 3, pp. 299–304, 2011.
- D. Bui, H. E. Brown, R. B. Harris, and E. Oren, “Serologic evidence for fecal-oral transmission of Helicobacter pylori,” The American Journal of Tropical Medicine and Hygiene, vol. 94, no. 1, pp. 82–88, 2016.
- J. C. Atherton, P. Cao, R. M. Peek Jr., M. K. R. Tummuru, M. J. Blaser, and T. L. Cover, “Mosaicism in vacuolating cytotoxin alleles of Helicobacter-pylori—Association of specific vacA types with cytotoxin production and peptic ulceration,” The Journal of Biological Chemistry, vol. 270, no. 30, pp. 17771–17777, 1995.
- N. S. Akopyants, S. W. Clifton, D. Kersulyte et al., “Analyses of the cag pathogenicity island of Helicobacter pylori,” Molecular Microbiology, vol. 28, no. 1, pp. 37–53, 1998.
- R. M. Peek Jr., M. J. Blaser, D. J. Mays et al., “Helicobacter pylori strain-specific genotypes and modulation of the gastric epithelial cell cycle,” Cancer Research, vol. 59, no. 24, pp. 6124–6131, 1999.
- J. G. Kusters, A. H. M. van Vliet, and E. J. Kuipers, “Pathogenesis of Helicobacter pylori infection,” Clinical Microbiology Reviews, vol. 19, no. 3, pp. 449–490, 2006.
- E. Mnich, M. Kowalewicz-Kulbat, P. Sicińska et al., “Impact of Helicobacter pylori on the healing process of the gastric barrier,” World Journal of Gastroenterology, vol. 22, no. 33, pp. 7536–7558, 2016.
- D. Y. Graham, “Therapy of Helicobacter pylori: current status and issues,” Gastroenterology, vol. 118, no. 2, supplement 1, pp. S2–S8, 2000.
- T. Fukai, A. Marumo, K. Kaitou, T. Kanda, S. Terada, and T. Nomura, “Anti-Helicobacter pylori flavonoids from licorice extract,” Life Sciences, vol. 71, no. 12, pp. 1449–1463, 2002.
- A. Nostro, L. Cellini, S. Di Bartolomeo et al., “Antibacterial effect of plant extracts against Helicobacter pylori,” Phytotherapy Research, vol. 19, no. 3, pp. 198–202, 2005.
- M. P. Germanò, R. Sanogo, M. Guglielmo, R. De Pasquale, G. Crisafi, and G. Bisignano, “Effects of Pteleopsis suberosa extracts on experimental gastric ulcers and Helicobacter pylori growth,” Journal of Ethnopharmacology, vol. 59, no. 3, pp. 167–172, 1998.
- Y.-C. Wang, “Medicinal plant activity on Helicobacter pylori related diseases,” World Journal of Gastroenterology, vol. 20, no. 30, pp. 10368–10382, 2014.
- M. Zamani and V. Zamani, “Helicobacter pylori antibiotic resistance: can herbal medicine be an alternative for the treatment?” Journal of Research in Medical Sciences, vol. 21, no. 1, p. 97, 2016.
- C. A. González, N. Sala, and T. Rokkas, “Gastric cancer: epidemiologic aspects,” Helicobacter, vol. 18, supplement 1, pp. 34–38, 2013.
- C. A. Gonzalez, L. Lujan-Barroso, H. B. Bueno-De-Mesquita et al., “Fruit and vegetable intake and the risk of gastric adenocarcinoma: a reanalysis of the european prospective investigation into cancer and nutrition (EPIC-EURGAST) study after a longer follow-up,” International Journal of Cancer, vol. 131, no. 12, pp. 2910–2919, 2012.
- C. De Martel, J. Ferlay, S. Franceschi et al., “Global burden of cancers attributable to infections in 2008: a review and synthetic analysis,” The Lancet Oncology, vol. 13, no. 6, pp. 607–615, 2012.
- G. Guzeldag, L. Kadioglu, A. Mercimek, and F. Matyar, “Preliminary examination of herbal extracts on the inhibition of Helicobacter pylori,” African Journal of Traditional, Complementary and Alternative Medicines, vol. 11, no. 1, pp. 93–96, 2014.
- Y. Li, C. Xu, Q. A. Zhang, J. Y. Liu, and R. X. Tan, “In vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines used to treat ulcer diseases,” Journal of Ethnopharmacology, vol. 98, no. 3, pp. 329–333, 2005.
- A. L. Rozza, T. D. M. Moraes, H. Kushima et al., “Gastroprotective mechanisms of Citrus lemon (Rutaceae) essential oil and its majority compounds limonene and β-pinene: involvement of heat-shock protein-70, vasoactive intestinal peptide, glutathione, sulfhydryl compounds, nitric oxide and prostaglandin E2,” Chemico-Biological Interactions, vol. 189, no. 1-2, pp. 82–89, 2011.
- F. Bonamin, T. M. Moraes, R. C. Dos Santos et al., “The effect of a minor constituent of essential oil from Citrus aurantium: the role of β-myrcene in preventing peptic ulcer disease,” Chemico-Biological Interactions, vol. 212, no. 1, pp. 11–19, 2014.
- Y.-S. Lee, J.-Y. Huh, S.-H. Nam, S.-K. Moon, and S.-B. Lee, “Enzymatic bioconversion of citrus hesperidin by Aspergillus sojae naringinase: enhanced solubility of hesperetin-7-O-glucoside with in vitro inhibition of human intestinal maltase, HMG-CoA reductase, and growth of Helicobacter pylori,” Food Chemistry, vol. 135, no. 4, pp. 2253–2259, 2012.
- E. Touati, V. Michel, M. Correia et al., “Boropinic acid, a novel inhibitor of Helicobacter pylori stomach colonization,” Journal of Antimicrobial Chemotherapy, vol. 64, no. 1, pp. 210–211, 2009.
- H. Nakagawa, Y. Takaishi, N. Tanaka, K. Tsuchiya, H. Shibata, and T. Higuti, “Chemical constituents from the peels of Citrus sudachi,” Journal of Natural Products, vol. 69, no. 8, pp. 1177–1179, 2006.
- K. Takeda, H. Utsunomiya, S. Kakiuchi et al., “Citrus auraptene reduces Helicobacter pylori colonization of glandular stomach lesions in Mongolian gerbils,” Journal of Oleo Science, vol. 56, no. 5, pp. 253–260, 2007.
- H. Sekiguchi, K. Irie, and A. Murakami, “Suppression of CD74 expression and helicobacter pylori adhesion by auraptene targeting serum starvation-activated ERK1/2 in NCI-N87 gastric carcinoma cells,” Bioscience, Biotechnology and Biochemistry, vol. 74, no. 5, pp. 1018–1024, 2010.
- H. Sekiguchi, F. Takabayashi, K. Irie, and A. Murakami, “Auraptene attenuates gastritis via reduction of helicobacter pylori colonization and pro-inflammatory mediator production in C57BL/6 mice,” Journal of Medicinal Food, vol. 15, no. 7, pp. 658–663, 2012.
- H. Sekiguchi, K. Washida, and A. Murakami, “Suppressive effects of selected food phytochemicals on CD74 expression in NCI-N87 gastric carcinoma cells,” Journal of Clinical Biochemistry and Nutrition, vol. 43, no. 2, pp. 109–117, 2008.
- F. Nabati, F. Mojab, M. Habibi-Rezaei, K. Bagherzadeh, M. Amanlou, and B. Yousefi, “Large scale screening of commonly used Iranian traditional medicinal plants against urease activity,” DARU, Journal of Pharmaceutical Sciences, vol. 20, no. 1, article 72, 2012.
- M. Biglar, H. Sufi, K. Bagherzadeh, M. Amanlou, and F. Mojab, “Screening of 20 commonly used Iranian traditional medicinal plants against urease,” Iranian Journal of Pharmaceutical Research, vol. 13, pp. 195–198, 2014.
Copyright © 2017 Giuseppina Mandalari et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.