A significant issue concerning the use of epigenetic targeting agents in conditions such as rheumatic disease is that these are chronic conditions and require long-term treatment regimens. Nutrition-based interventions, therefore, may provide a novel therapeutic avenue of approach with this factor in mind. A large number of naturally occurring bioactive compounds have been shown to inhibit various members of the epigenetic machinery [83
]. Evidence to link these naturally occurring compounds with potential patient benefit in rheumatic disease is now emerging.
One of the most extensively studied of these compounds is curcumin, a natural polyphenol occurring in turmeric. Conversely, this compound has been shown to inhibit both HDACs and KATs (reviewed in [84
]). Two pilot studies have been conducted in patients with rheumatic disease. In the first study, the safety and effectiveness of curcumin alone and in combination with diclofenac sodium were evaluated in patients with active RA [85
]. Forty-five patients with RA were randomly assigned to one of three groups with patients receiving curcumin (500 mg) and diclofenac sodium (50 mg) alone or in combination. The primary endpoint in this study was a reduction in Disease Activity Score (DAS), and secondary endpoints involved the assessment of American College of Rheumatology (ACR) criteria for reductions in tenderness and joint swelling scores. Patients received treatment for an 8-week period. Overall, all groups showed significant improvement in all tested ACR components and in their DASs. Critically, the patients who received curcumin showed the best improvements and were significantly better than the patients who received diclofenac sodium. Most importantly, curcumin treatment was found to be safe and was not related to any adverse events [85
]. A second study examined the effect of Meriva (Thorne Research, Inc., Dover, ID, USA), a formulation of curcumin complexed with phosphatidylcholine, on joint pain and improvement in joint function of patients with OA [86
]. In this study, 100 patients received treatment with this compound for a period of 8 months. Clinical endpoints were WOMAC (Western Ontario and McMaster Universities Arthritis Index) score, Karnofsky Performance Scale Index, and treadmill walking performance. At the end of the study, Meriva was shown to significantly improve all clinical endpoints. Secondary endpoints examined were a panel of inflammatory markers. Meriva was found to significantly decrease the expression of IL-6, IL-1β, sCD40L, and sVCAM-1 (soluble form of vascular cell adhesion molecule-1) in patients, whereas the control arm had no significant alterations in the levels of these pro-inflammatory markers [86
]. These results indicate that cur-cumin may have important potential in the treatment of rheumatic disease. It must be noted that, in pancreatic cancer cells in vitro
, a curcumin analog has also been shown to induce the expression of mIR-146a. As previously discussed, this miRNA may be a critical component in rheumatic disease, and it will be important to determine whether curcumin or curcumin-based analogs can affect this miRNA within the rheumatic disease setting.
Another novel bioactive dietary compound present in many pigmented fruits and vegetables is delphinidin (reviewed in [87
]), which has been shown to be a specific inhibitor of K-acetyltransferases KAT3A/KAT3B [88
]. Critically, delphinidin has also been shown to suppress inflammatory signaling via prevention of NF-κB acetylation in a human RA FLS cell line [88
]. Similar effects on NF-κB have been seen for this compound in prostate cells both in vitro
and in vivo
], indicating that this bioactive compound may also have potential utility in the treatment of rheumatic disease or other autoimmune conditions, particularly those that are associated with NF-B-mediated inflammation.
Resveratrol is another natural compound that has been extensively studied for its potential utility in the management of diabetes. This compound is thought to be an activator of SIRT-1, but this view has since been called into question [90
]. It has since been determined to function by inhibiting cAMP phosphodiesterases [91
], and, as a consequence, levels of NAD+
increase with concomitant increased SIRT-1 activity. Nevertheless, a large body of evidence demonstrates the potential efficacy of this compound in modulating pro-inflammatory effects in arthritis, suggesting that further studies will be required to determine the true nature of this compound.
Sulforaphane (SFN) is a naturally occurring organosulfur compound that has been shown to inhibit HDACs (reviewed in [84
]). According to the ClinicalTrials.gov website [93
], several clinical trials (for example, NCT01543074
) are currently recruiting or will be recruiting in the near future to examine the effects of SFN in patients, but so far there have been no clinical trials on the potential of this compound in auto-immune disease. Of particular interest, NCT01357070 is currently recruiting patients to examine the effect of broccoli sprout on the blood levels of SFN to reduce responsiveness of patient immune systems. Specifically, the trial will examine, as a primary outcome, the resistance of leukocytes to inflammatory activation following an experimental stress following the consumption of a 'broccoli smoothie' containing SFN to determine whether it can protect white blood cells from becoming activated in the presence of an experimental stress and how long this protective effect lasts. Nevertheless, SFN has been shown to have effects on the immune system. It has been shown to inhibit the Th2 immune response in ovalbumin-induced asthma [94
]. The potential utility of this compound in the treatment of rheumatoid disease was demonstrated recently in an experimental mouse model of arthritis [95
]. In vitro
studies first demonstrated that RA FLSs treated with SFN resulted in the induction of apoptosis by reducing the levels of the anti-apoptotic protein Bcl-2 while inducing levels of pro-apoptotic p53 and Bax and decreasing levels of a pAkt [95
]. In contrast, activated T cells, which are well established as contributing to joint destruction in RA, were insensitive to SFN-induced apoptosis [95
]. Most importantly, SFN treatment of activated T cells was associated with a suppression of both cell proliferation and the expression of pro-inflammatory cytokines in these activated T cells [95
]. The authors subsequently examined the effects of SFN on collagen-induced arthritis (CIA) in mice. Using intra-peritoneal injection of SFN, the authors demonstrated that this compound ameliorated the effects of CIA with lower degrees of inflammation, synovial hyperplasia, pannus formation, and bone destruction compared with vehicle alone [95
]. This was accompanied by reduced T-cell proliferative responses and lowered secretion of pro-inflammatory cytokines such as IL-17, TNFα, IL-6, and IFNα [95
]. To validate these observations, the authors reexamined the effects of SFN in a passive model of RA (RA induced by injections of anti-CII antibody). Again, the severity of the RA was reduced significantly by SFN, and the peak arthritis severity scores were 10.3 ± 2.8 (mean ± standard deviation) in vehicle-treated mice versus 5.5 ± 2.1 in SFN-treated mice [95
]. Although effectiveness was demonstrated, it must be noted that there were no apparent adverse effects following administration of SFN, including changes in weight, physical appearance, or behavior [95
], thus indicating that SFN may have significant potential for the treatment of patients with RA. However, it must be noted that, in this paper, the authors did not determine whether the effects of SFN were a result of its HDACi activity versus its other known activities such as its ability to induce phase II antioxidant and detoxification enzymes [96