Nutriceutical pharmacologyAnti-oxidant and anti-inflammatory effects of cinnamaldehyde and eugenol on mononuclear cells of rheumatoid arthritis patients
Graphical abstract
Introduction
Rheumatoid arthritis (RA), a severe disabling arthritis is characterized by synovial infiltration and hyperplasia, thus leading to progressive destruction of articular tissues (Vivar and Van Vollenhoven, 2014). It affects around 1–2% of the world population, with women being 3 times more susceptible than man, probably due to the effect of female hormones on the activity of immune cells (Ngo et al., 2014). Although the etiology of RA is still not completely understood but some reports confirm the role of macrophages, T cells and B cells in the destruction of bone and cartilage (Hu et al., 2013). This autoimmune disorder is characterized by the presence of rheumatoid factor (antibody against IgG/IgM) and anti-citullinated peptide antibodies (ACPA) (Rantapää‐Dahlqvist et al., 2003). Activation of CD4+T cells by the arthritogenic agent (microbial or self-antigen) drives the autoimmune attack in the joints (Ahmed et al., 2017). Pro-inflammatory cytokines produced by activated T cells cause macrophages to release inflammatory mediators which in turn leads to secondary inflammatory injuries in arthritis (Chun et al., 2016).
The inflammatory cascade is also associated with the activation of oxidant generating enzymes (NADPH oxidase, xanthine oxidase, myeloperoxidase) thus promoting the production of reactive oxygen (ROS) and nitrogen (RNS) species (Fay et al., 2006). These reactive species are involved in cellular damage in joint tissues via various independent mechanisms such as depletion of antioxidants, lipid peroxidation, protein oxidation and DNA damage (Mahajan and Tandon, 2004). Thus inflammatory mediators and reactive species have direct or indirect effects on the pathophysiology of RA.
Non-steroidal anti-inflammatory drugs (NSAIDs) and disease modifying anti-rheumatic drugs (DMARDs) used for the treatment of RA are associated with various adverse drugs reaction, for example gastrointestinal ulcers, cardiovascular complications, and emergence of opportunistic infections due to immunosuppressants (Desai et al., 2014). Moreover, biologics such as TNF-α inhibitors, IL-1ß inhibitors, IL-6 inhibitors are also used in the treatment of RA. However their cost, side effects and interference in immune defense response limit their use (Li et al., 2013). Therefore, there is a need to evaluate anti-arthritic efficacy of natural compounds which are relatively safe, tolerable and easily accessible.
Cinnamaldehyde is a bioactive compound isolated from the bark of Cinnamomum cassia (Hancı et al., 2016). It has been used in the manufacturing industry as a spice and flavoring agent in beverages, sweets, ice-creams and chewing gums (Roth-Walter et al., 2014). Eugenol is a phenylpropanoid compound present in honey and essential oil of spices such as Syzgium aromaticum, Cinnamomum verum and Pimenta racemosa (Jaganathan et al., 2011). Both these compounds have been used in traditional medical practices (local analgesic and for the treatment of disturbances in blood circulation, dyspepsia, inflammation, gastritis) due to their anti-fungal, anti-bacterial, anti-inflammatory, anti-mutagenic and anti-oxidant effects (Jaganathan et al., 2011, Roth-Walter et al., 2014).
In our previous publication we have shown that cinnamaldehyde and eugenol have ameliorated oxidative stress and inflammation in collagen induced arthritis in rats (Mateen et al., 2019). In the present study keeping into consideration that RA is a systemic disorder, PBMCs obtained from RA patients were treated with various concentrations of cinnamaldehyde and eugenol in order to determine their effect on oxidant-antioxidant status and secretion of pro-inflammatory cytokines.
Section snippets
Human subjects
The study protocol was approved from the Institutional Ethical Committee of Jawaharlal Nehru Medical College, A.M.U. Informed consent was obtained from all the participants of the study. Blood was obtained from healthy controls (n = 10) and RA patients (n = 20) who attended the Orthopaedics Out Patient Department (OPD) of Jawaharlal Nehru Medical College and Hospital, Aligarh, India. Patients were diagnosed according to the European League Against Rheumatism (EULAR) 2010 classification criteria
Effect of cinnamaldehyde and eugenol on cell viability
To examine the effect of cinnamaldehyde and eugenol on the viability of PBMCs, MTT assay was performed. As shown in Fig. 1[A]. 10 20, 40 µM of cinnamaldehyde and eugenol caused no significant change in the viability of PBMCs. Therefore, for further experiments 10, 20 and 40 µM of cinnamaldehyde and eugenol were used.
Effect of cinnamaldehyde and eugenol on cytokine level
The level of pro-inflammatory cytokines TNF-α and IL-6 [Fig. 1B and C] were monitored in the 24-h culture supernatant of PBMCs. RA patients showed significantly higher levels of
Discussion
Rheumatoid arthritis is an inflammatory autoimmune disorder. Reactive oxygen species and pro-inflammatory cytokines have been shown to play an important role in the pathophysiology of RA (Mateen et al., 2016, Mateen et al., 2017). Various natural compounds have been shown to impart their antioxidant and anti-inflammatory effects in the management of many diseases (Umar et al., 2013, Umar et al., 2012, Wang et al., 2017). The results of the present study showed heightened inflammatory state in
Conclusion
Cinnamaldehyde and eugenol were effective in suppressing the secretion of pro-inflammatory cytokines from the cultured PBMCs of RA patients. These compounds have also reduced the neutralizing reactive oxygen/nitrogen species formation which in turn has ameliorated biomolecular oxidation and antioxidant defence response in the PBMC culture of RA patients. Thus these compounds have potential to be used as an adjunct in the management of RA by virtue of their free radical scavenging and
Acknowledgement
Assistance from the Institution (AMU) as well as infrastructural support from DST-FIST to the department is duly acknowledged. The authors extend their appreciation to the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia for funding this work through research group project number RGP-215. The authors are grateful to Chairman, Dept. of Physiology for allowing us to avail various lab facilities. The authors are also thankful to Dr Saba Tufail, Dr. Asif Zaman, Mr. Mohd.
Author contributions
Conceived and designed the experiments: SMateen, SMoin. Performed the experiments: SMateen, MTR, SS, SK, FMH. Analyzed the data: SMateen, MTR, SMoin. Contributed samples/reagents/materials/analysis tools: SMoin, SSN, AQK, MTR, SK, FMH. Wrote the paper: SMateen, MTR, SSN.
Conflict of interest
The authors declare that they have no conflict of interest.
Author agreement
The manuscript entitled ‘Anti-oxidant and Anti-inflammatory effects of Cinnamaldehyde and Eugenol on Mononuclear Cells of Rheumatoid Arthritis Patients’ was reviewed by all authors, agreed with its content and agreed to its submission in European journal of pharmacology.
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