ReviewThe potential use of l-sulforaphane for the treatment of chronic inflammatory diseases: A review of the clinical evidence
Introduction
Chronic inflammatory diseases is a collective term used to define diseases where the immune response fails to regulate normal acute inflammation leading to a state of unresolved, prolonged inflammation. Such diseases include rheumatoid arthritis, inflammatory bowel disease, respiratory conditions, cardiovascular diseases, diabetes and cancer, accounting for approximately 70% of all global deaths annually [1]. Although non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids treatments are available neither are sustainable, and are associated with side effects. Therefore, there is great interest in investigating novel therapies for the management of chronic inflammatory diseases.
Since the early 1990s, accumulating evidence has indicated a wide-range of health benefits associated with the consumption of cruciferous vegetables, including reduced risk of cardiovascular disease [2], diabetes [3] and certain types of cancers [4], [5], [6]. These beneficial properties have been largely attributed to the high concentration of glucoraphanin, an isothiocyanate and precursor to the active compound l-sulforaphane (LSF) [7].
LSF and its metabolites are formed via the activation of the enzyme myrosinase [8] (Fig. 1). Myrosinase is usually activated upon mechanical plant cell wall breakage or via other myrosinase-like enzymes present in the gut microbiota upon digestion [9] and accounts for 60–80% of the hydrolysis of glucoraphanin.
Cruciferous vegetables belong to the Brassicaceae family and include vegetables such as broccoli, cauliflower, and kale. Broccoli contains significantly higher concentrations of glucoraphanin compared to other cruciferous vegetables [10]. This has resulted in a recent spike in clinical trials with dietary supplements of broccoli florets or sprouts, or biologically modified products rich in LSF, to determine the efficacy of LSF in the prevention or treatment of chronic inflammatory diseases.
Section snippets
Pre-clinical studies with l-sulforaphane
The effectiveness of LSF has been extensively investigated in vitro and in a range of animal models of disease, demonstrating anti-inflammatory and antioxidant properties as well as more recently its ability to modify chromatin architecture.
The anti-inflammatory effects of LSF were demonstrated by Park and co-workers [11] who examined LSF in an ovalbumin-induced murine asthma model, finding that LSF significantly dampened the Th2 response through a reduction in interleukin (IL)-4 and IL-5 as
Clinical trials with l-sulforaphane and precursor-containing supplements
Understanding the potential clinical benefits of LSF has become an exciting area of research. LSF supplements have been examined in healthy adults as well as for a range of conditions including autism [16], schizophrenia [17], and chronic inflammatory diseases such as cancer, allergic airways diseases, and diabetes. To date, most of the studies that have been completed or are currently ongoing represent either pilot, phase 1, or phase 2 trials. This is with the exception of a phase 4 trial for
Antioxidant capacity
Historically, LSF has been recognized for its antioxidant capacity by inducing phase II enzymes in the detoxification process [37]. Phase II enzymes equilibrate ROS imbalance via the activation of the kelch-like ECH-associated protein 1 (Keap1)/Nrf2 pathway [38]. Upon consumption of cruciferous vegetables, LSF enters cells and binds with Keap1 and destabilises its bond with the inactivate Nrf2-Keap1 protein. Nrf2 protein translocates into the nucleus to bind with the antioxidant response
Limitations in clinical trials with l-sulforaphane
Evaluating the clinical efficacy of LSF for chronic inflammatory diseases is difficult due to the diversity in study designs, sample size, target populations recruited, and source, concentration, and duration of consumption of LSF. The number of ongoing clinical trials of LSF will add to the already existing evidence base however, concerted efforts are needed to standardise the way in which these trials are undertaken. Particularly important considerations for future clinical trials of LSF are
Conclusion
To date, clinical studies with LSF or relevant precursor-containing extracts have yielded promising yet, inconsistent results. These are largely due to differences in the study designs, source (bioactivity), and dose of LSF, and the disease context and/or target population studied. Nevertheless, the beneficial effects observed in certain diseases and the lack of serious side effects observed to date is exciting. Therefore, the potential for LSF to mediate important clinical benefits in those
Sources of support
McCord Research (Iowa, USA), Australian Research Council Future Fellowship, NHMRC career development fellowship, Australian Government Research Training Program Scholarship.
Conflicts of interest
Epigenomic Medicine Program (TCK) is supported financially by McCord Research (Iowa, USA), which has a commercial interest in sulforaphane. PVL, KN, and NM have no conflicts of interests.
Contribution of authors
NM produced the draft. KS, PVL, and TCK contributed equally to iterations of editing the manuscript.
Acknowledgements
TCK is supported by an Australian Research Council Future Fellowship and the Epigenomic Medicine Laboratory is supported by McCord Research (Iowa, USA). PVL is a NHMRC CDF2 recipient. NM is supported by Australian Government Research Training Program Scholarship.
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These authors contributed equally to this work.