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Open Access

Cyclooxygenase inhibition with curcumin in Helicobacter pylori infection

  • António Mário Santos1, 2Email author,
  • Teresa Lopes2,
  • Mónica Oleastro3,
  • Teresa Pereira4,
  • Carolina Coimbra Alves2,
  • Elsa Seixas2,
  • Paula Chaves4,
  • Jorge Machado3 and
  • António Sousa Guerreiro1, 2
Nutrire201843:7

https://doi.org/10.1186/s41110-018-0070-5

Received: 14 August 2017

Accepted: 8 February 2018

Published: 5 May 2018

Abstract

Background

Helicobacter pylori (H. pylori) infection increases the expression of cyclooxygenase-2 (COX-2) on the host’s gastric mucosa. The inhibition of COX-2 activity with natural products would be a major advantage. This study aims to clarify the possible effect of curcumin on COX-2 inhibition in gastric mucosa of H. pylori infected mice.

Methods

We inoculated 30 pathogen-free male C57BL/6 mice with H. pylori (SS1 Sidney strain) that were randomly divided in two different groups: infected group (IG) treated with phosphate-buffered saline (PBS) (n = 15) and infected group treated with curcumin 500 mg/kg (IG + C) (n = 15). A group of 15 non-infected mice were used as control (CG). Two weeks post-infection, both IG and CG groups received 0.5 ml of PBS, while the IG + C group received curcumin for 6, 18, and 27 weeks.

Results

The analysis by immunohistochemistry and by PCR array at 6, 18, and 27 weeks post-infection showed a significant increase on COX-2 expression on the IG mice compared to the CG mice. The group treated with curcumin (IG + C) showed a significant downregulation of COX-2 at all points of the experiment, when compared to the IG + C mice.

Conclusion

Chronic H. pylori infection induces a significant increase in COX-2 expression. Treatment with curcumin significantly decreases the COX-2 expression, and the addition of curcumin to the diet may be an interesting approach for areas of high H. pylori prevalence.

Keywords

H. pylori CurcuminExperimental modelCOX-2

Background

Helicobacter pylori (H. pylori) infection is associated with several gastroduodenal disorders such as chronic gastritis, peptic ulcer disease, MALT lymphoma, and gastric distal carcinoma [1, 2]. Nevertheless, the exact mechanisms involved in the development of these disorders remain unclear. It has been reported that H. pylori increases cell proliferation of the gastric mucosa and the eradication of the infection returns cell proliferation to normal levels [35]. The hyperplastic changes observed in H. pylori-induced gastritis are thought to be associated with pre-cancerous changes [6, 7]. Although the precise mechanisms involved in these changes are not all yet clear, it has been described that cyclooxygenase-2 (COX-2) is implicated in these alterations observed in gastric mucosa of mice infected with H. pylori [8].

COX-2 whose expression induced by cytokines, growth factors, and tumor promoters has been shown to play a role as an immediate-early response in inflammation [9].

Several studies in humans and animals show that H. pylori upregulates the expression of COX-2 both at mRNA and protein levels, which might be one of the mechanisms leading to several gastric diseases [10].

So far, the clinical approach to target COX-2 has been via inhibition of its activity with non-steroidal inflammatory drugs (NSAIDs).

It was found that the prolonged intake of NSAIDs was able to produce serious side effects and also that the chronic use of salicylates can damage the gastric mucosa [11] and produce gastrointestinal bleeding [12]. For this reason, the medical community looks with concern to this class of drugs.

Despite all these facts, the inhibition of COX-2 would be of major interest in many pathological conditions, in which its expression is chronically upregulated, such as H. pylori gastritis, autoimmune diseases, and several types of cancer [13].

Targeting COX-2 expression with natural compounds may therefore represent a promising strategy, by which the same preventive and therapeutic benefits may be obtained although avoiding the adverse side effects of COX-2 enzymatic inhibition.

Nowadays, there is a global interest in nutraceuticals, a huge source of biologically active molecules that remain largely unexplored, with proven anti-inflammatory properties and whose role is being increasingly recognized in improving health care [1416].

Curcumin, the nutraceutical used in the present study, is the main component of the plant Curcuma longa, a gold-colored spice commonly used in the Indian subcontinent, not only for health care but also for the preservation of food. This nutraceutic has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities. These effects are mediated through the regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes [1720].

The high prevalence of H. pylori infection all over the world [21], the high costs of treatment, and the high level of treatment failure due to antibiotic resistance lead the scientists trying to develop a vaccine against H. pylori infection. Although the large amount of investigation was produced in this field, so far, this kind of vaccine is not yet available.

So, it would be of major interest to find a treatment with anti-inflammatory activity of plant-derived molecules, like curcumin, modulating the COX-2 activity but without the side effects of NSAIDs.

The aim of the present work was to study the expression of COX-2 during treatment with curcumin on gastric mucosa of mice in H. pylori experimental chronic infection model.

Methods

Animal housing and study design

A total of 45 pathogen-free male C57BL/6 5-week-old mice (Harlan Laboratories, Castellar, Spain) were used in compliance with the guidelines and protocols approved by the National Animal Care Committee from the Portuguese General Veterinary Direction. After arrival, the mice were randomly divided in cages (5 mice per cage) with ad libitum access to acidified tap water (1 bottle per cage) and sterilized standard diet (Mmucedolasrl–4RF21 certificate batch: 250202). Then, the mice were kept for 2 weeks for acclimatization purposes before starting the experimental procedure. The animal facility has a positive pressure local exhaust ventilation, with 15–20 air changes per hour, room temperature between 21 and 24 °C, regulated relative humidity (55% ± 10%), and an artificial standard 12 h light/12 h dark cycle of 250 lx intensity.

After the acclimatization period and using a 20-gauge ballpoint metal feeding tube (Harvard Apparatus, Inc., Holliston, Mass.), 30 mice were inoculated intragastrically, on three consecutive days, with 0.1 ml of H. pylori SS1 strain (Sidney strain) cell suspension containing 108 cfu/ml. The presence or absence of active H. pylori infection was evaluated for all mice 1 week after the infection and then at 6, 18, and 27 weeks post-infection, before euthanasia, with an adapted 13C-UBT, as previously described [22].

Two weeks later, the infected mice were randomly divided in two different groups: infected group treated with phosphate-buffered saline (PBS; IG), n = 15, and infected group treated with curcumin (IG + C), n = 15. The remaining 15 non-infected mice were used as control group (CG).

The CG and the IG groups received 0.5 ml of PBS, while the IG + C group received 0.5 ml of a lipidic solution of curcumin (Sigma-Aldrich, Sintra, Portugal) (500 mg/kg) [19]. The two regimens were given three times a week, for 6, 18, and 27 weeks post-infection by gavage.

Five mice from each group were euthanized at 6, 18, and 27 weeks post-infection.

Sampling

Animals were fasted for 14 h and then euthanized by cervical dislocation. For each mouse, half of the stomach was placed in buffered formalin to be fully processed for H. pylori and COX-2 immunohistochemistry analysis and the remaining half was immediately conserved at − 80 °C in RTL buffer (Qiagen GmbH, Hilden, Germany), with 2-mercaptoethanol (Sigma-Aldrich, Sintra, Portugal), for RNA extraction.

Immunohistochemistry

Sections of buffered formalin-fixed paraffin-embedded tissue blocks with 2 μm thickness were cut onto Superfrost Plus slides. After baking in an oven, the sections were de-waxed, rehydrated, and subjected to epitope antigen retrieval (20 min, 94 °C) with Target Retrieval Solution High pH 50× Envision™ Flex (Dako, Ref.: DM828) in a pre-treatment module PTlink (Dako, Code No. PT10130). Endogenous peroxidase was blocked with 2% H2O2 in absolute methanol for 10 min. Immunostaining was performed by the c.

Immunohistochemistry for H. pylori was done using a primary polyclonal rabbit anti-H. pylori (Dako B0471, Glostrup, Denmark) incubated for 30 min at room temperature. As positive control, a mouse gastric specimen previously known to be positive for H. pylori was used. For negative control, primary antibody was omitted during the staining. Immunohistochemistry for COX-2 was done using a primary rabbit monoclonal anti-COX-2, clone SP21 (Cell Marque 240R-14, 1:1500), and incubated overnight at 4 °C temperature. An appropriate positive control was used. For negative control, primary antibody was omitted during the staining. The visualization was done using labeled polymer HRP anti-rabbit (Dako EnVision™ K4011) detection staining system at room temperature for 30 min and DAB (3,3′-diaminobenzidine). Sections were counterstained with Mayer’s hematoxylin.

The area of immunostaining was accessed with image software analysis Aperio ImageScope™ v11.1.2.760. Positive area of immunostaining was measured only when software analysis detected strong staining [23].

Real-time PCR arrays

For PCR arrays, three mice from each group, CG, IG, and IG + C, were randomly selected and tested individually. Total RNA from stomach mice samples was extracted using the RNeasy Mini kit (QiagenGMbH, Hilden, Germany), including the DNase I digestion step to eliminate residual genomic DNA. Integrity and concentration of each RNA sample was analyzed in the Agilent 2100 Bioanalyzer. Then, 25.0 ng to 5.0 μg RNA were reverse-transcribed to single-stranded cDNA using the RT2 First Strand kit (Qiagen, Germany). All procedures were performed according to manufacturer’s protocols.

Analysis of expression of COX-2gene as well as of five housekeeping genes (HKG), was performed by PCR array, using the RT2 Profiler PCR Array Mouse Inflammatory response and Immunity pathway (SABioscience, Qiagen), in a 384-well format, using the Applied Biosystems 7900HT Fast Real-Time PCR System. Data was normalized to the mean values of the five HKG, and the relative amount of RNA was calculated using the 2−ΔCt method. Fold change calculations were done using SABiosciences’ data analysis software, which automatically calculates the fold change in gene expression between the infected non-treated mice and the control group (IG versus CG) and between the infected and curcumin-treated mice and the control group (IG + C versus CG). Fold change values greater than one indicate an upregulation, while fold changes less than one indicate a downregulation [23].

Statistical analysis.

Differences were tested by Student’s t test, being considered as statistically significant when P < 0.05. Results are expressed as averages ± standard deviations (SD) of n observations.

Results

H. pylori status

All the 30 inoculated mice (IG and IG + C) were H. pylori-positive by 13C-urea breath test (data not shown) and by immunohistochemistry (Fig. 1). All mice from control group (CG) were negative for both methods.
Figure 1
Fig. 1

Immunohistochemistry of the gastric mucosa of Helicobacter pylori infected mouse, × 100 (black arrows indicate bacteria)

COX-2 immunostaining

The area of COX-2 immunostaining was accessed with the Aperio ImageScope software. The microscope image was digitalized by the software (Fig. 2a) and was automatically processed. When strong immunostaining was detected (Fig. 2b), the area was quantified (dark-brown areas) as number of pixels.
Figure 2
Fig. 2

Immunohistochemistry image of COX-2 quantification using Aperio ImageScope™ software on the gastric mucosa of Helicobacter pylori-infected mouse (× 100). Original microscope image (a) and the respective processed image by the software (b). Dark-brown area indicates strong positive quantified immunostaining

In the IG (PBS) group, the production of COX-2 was significantly upregulated (area of positive immunostaining pixels) at week 6 (393–544 × 103 pixels), week 18 (242–614 × 103 pixels), and week 27 (129–175 × 103 pixels) post-infection. The curcumin treatment significantly decreased the expression of COX-2 at all time points: 175–206 × 103 pixels (p = 0.0012) at week 6, 134–149 × 103 pixels (p = 0.0010) at week 18, and 87–97 × 103 pixels (p = 0.047) at week 27 (Fig. 3).
Figure 3
Fig. 3

Mean areas of immunostaining for COX-2 quantification using Aperio ImageScope™ software on the gastric mucosa of Helicobacter pylori-infected mice treated with either PBS (infected—IG) or curcumin (IG + C)

PCR array of COX-2

The analysis by PCR array of COX-2 showed at least a 50,000-fold increase in gene expression between the control group (CG) and the infected group (IG) of mice at 6, 18, and 27 weeks post-infection (IG vs CG) (Fig. 4).
Figure 4
Fig. 4

Fold change expression of COX-2 in the gastric mucosa as determined by PCR arrays and calculated using the 2−ΔCt method, comparing the Helicobacter pylori-infected non-treated mice (IG) and the infected and treated with curcumin mice (IG + C) versus non-infected mice (CG) at weeks 6, 18, and 27 post-infection. Values denote the means obtained for each of the mice analyzed in each group; each mouse was tested in duplicate (±SD). p < 0.005 for all the comparisons between the infected non-treated and the infected curcumin-treated groups

At all time points of the experiment, COX-2 gene expression in the curcumin-treated mice (IG + C) was still upregulated compared to the control group (CG); however, the levels of fold change significantly decreased on average at least 8000 times when compared to the fold change observed in the mice infected group (IG), with p values < 0.005 at all time points of the experiment (IG vs IG + C) (Fig. 4).

Discussion

As described previously, COX-2 is a key enzyme in the prostanoid synthesis. Under physiological conditions, it is only found in minor concentrations and is induced in several pathological conditions [24, 25] such as H. pylori infection. Our study shows that the mouse-adapted H. pylori SS1 strain seems to be very well adapted to the mice stomach milieu, which explains the high infection rate with this strain even after 27 weeks post-infection (100%), and we had a strong expression of COX-2 as early as 6 weeks post-infection and a similar result at 18 and 27 weeks post-infection. This increased expression was observed at mRNA expression level and also at the protein expression level. In H. pylori infection, both bacterial and host factors are believed to contribute to gastric mucosal damage. Regarding host factors, it is suspected that inflammatory responses may be involved in H. pylori-induced gastritis [2628]. Romano et al. [29] reported that adhesion of H. pylori on cultured gastric cancer MKN28 cells results in COX-2 mRNA expression. However, it is unclear whether the direct effect of H. pylori on gastric cells is crucial for COX-2 expression in vivo, because COX-2 protein was not expressed even at 2 weeks post-H. pylori infection in some experimental models [30].

The high and uncontrolled expression of COX-2 may induce tissue damage and tumor growth, and the suppression of COX-2 is related with the inhibition of gastric carcinoma cell growth. The administration of dietary curcumin to a human xenograft model in nude mice decreased metastasis of breast cancer to the lung, supported by the suppressed expression of NF-κB and COX-2 [31].

The use of all NSAIDs, selective and nonselective, is associated with a range of potential adverse effects, including an increased risk of adverse cardiovascular effects. Both COX-2 selective NSAIDs (coxibs) and nonselective NSAIDs may increase such risk. A survey made in our country showed that these drugs are widely prescribed, despite the potential harmful side effects [32].

The administration of anti-inflammatory COX-2 inhibitors to inhibit/modulate the COX-2 expression has been ineffective since the risks prevail over the benefits. Clinical demonstration of severe side effects due to the failure of the classical COX-2 inhibitors to discriminate between an aberrant pathological versus homeostatic functional activation state raised the concern that direct COX-2 enzymatic inhibition might not sufficiently represent an appropriate clinical strategy to target COX-2 [33].

Several nutraceuticals have been shown to exert modulatory effect on COX-2 at various levels of its molecular regulation, and therefore, they have been considered as an effective alternative strategy to control the pathogenic expression of COX-2 [34, 35]. The safety, tolerability, and non-toxicity of curcumin are well established not only in experimental models but also in human trials [3639].

In the present study, H. pylori infection increased the expression of COX-2 at all time points of the experiment while curcumin inhibited COX-2 expression at both mRNA and protein levels at all same time points of the chronic infection. It has been described that the anti-inflammatory mechanism of curcumin is in part due to is ability to suppress NF-KB pathway, the main regulator of the inflammatory response [40, 41]. Despite of that curcumin, also demonstrates direct inhibition activity of COX-2 [42, 43].

Conclusions

H. pylori upregulates the expression of COX-2 both at mRNA and protein levels which might be one of the mechanisms implicated in the development of gastric diseases.

Nutraceuticals, like curcumin, are currently receiving recognition as being beneficial in many diseases, and evidences indicate that the mechanism of action of natural compounds involves an extensive range of biological processes, including anti-inflammatory properties without the harmful effects of the NSAIDs.

Data from our study confirm the important role of curcumin in COX-2 downregulation in the chronic H. pylori mice infection.

As curcumin can inhibit COX-2 expression at both gene and protein expression without the secondary effects of the NSAIDs or COXIBs, we can conclude that the supplementation of diet in humans with curcumin may be a possible novel therapeutic approach against gastric inflammation induced by H. pylori infection. The supplementation of diet with this nutraceutical may be an interesting approach for areas of high H. pylori prevalence. Results from ongoing clinical trials will provide a deeper understanding of curcumin’s potential therapeutic properties.

Abbreviations

CG: 

Control group

COX-2: 

Cyclooxygenase-2

COXIBs: 

Highly selective COX-2 inhibitors

H. pylori

Helicobacter pylori

IG + C: 

Infected group plus curcumin

IG: 

Infected group

NSAIDs: 

Non-steroidal inflammatory drugs

PBS: 

Phosphate-buffered saline

PCR: 

Polymerase chain reaction

Declarations

Acknowledgements

Not applicable.

Funding

This work was supported by PTDC/SAU-OSM/66323/2006 research grant from Fundação para a Ciência e a Tecnologia (FCT), Portugal.

Availability of data and materials

The datasets generated used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

All authors made a significant contribution to the research and the development of the manuscript, helped design the study, and directed the study’s implementation, including quality assurance and control. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki) and protocol from the study which was approved by the National Animal Care Committee from the Portuguese General Veterinary Direction.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Serviço Medicina 4 Hospital Sta. Marta C H Lisboa Central, Lisbon, Portugal
(2)
Nova Medical School, Faculdade de Ciências Médicas, Lisbon, Portugal
(3)
Department of Infectious Diseases, National Institute of Health Dr. Ricardo Jorge, Lisbon, Portugal
(4)
Department of Pathology, Instituto Português de Oncologia de Francisco Gentil, Lisbon, Portugal

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