Nuclear factor-kappa B (NF-κB) is a ubiquitous transcription factor that is involved in inflammatory and immune responses, as well as in regulation of expression of many other genes related to cell survival, proliferation, and differentiation. In mammals, NF-κB comprises five subunits that can bind to promoter regions of target genes as homodimers or heterodimers. The most common dimer is the p50/p65 heterodimer. The several combinations of dimers that can be formed contribute to the heterogeneous regulation of NF-κB target genes, and this heterogeneity is further increased by interactions of the NF-κB dimers with other transcription factors, such as steroid hormone receptors, activator protein-1 (AP-1), and cAMP response element binding protein (CREB). In the thyroid, several studies have demonstrated the involvement of NF-κB in thyroid autoimmunity, thyroid cancer, and thyroid-specific gene regulation. The role of NF-κB in thyroid autoimmunity was hypothesized more than 20 years ago, after the finding that the binding of distinct NF-κB heterodimers to the major histocompatibility complex class I gene is hormonally regulated. Further studies have shown increased activity of NF-κB in thyroid autoimmune diseases and in thyroid orbitopathy. Increased activity of NF-κB has also been observed in thyroid cancer, where it correlates with a more aggressive pattern. Of particular interest, mutation of some oncogenes or tumor suppressor genes involved in thyroid carcinogenesis results in constitutive activation of the NF-κB pathway. More recently, it has been shown that NF-κB also has a role in thyroid physiology, as it is fundamental for the expression of the main thyroid-specific genes, such as sodium iodide symporter, thyroid peroxidase, thyroglobulin, Pax8, and TTF-1 (NKX2-1).

Previous studies have shown that quercetin inhibits thyroid function both in vitro and in vivo. An attempt to evaluate the effect of quercetin at the promoter level of the thyroid-specific genes led to the observation that this compound induces the basal activity of the reporter vector. Therefore, the action of quercetin has been evaluated on the basal activity of several reporter vectors: The PGL3 basic, promoter and control vectors from Promega, and a pSV-based chloramphenicol acetyltransferase (CAT) reporter vector. In the Fisher Rat Thyroid cell Line FRTL-5 thyroid cells transiently transfected, quercetin 10 μM increased the basal activity of all the reporter vectors evaluated, although the degree of the effect was significantly different among them. The analysis of the difference among the regulatory regions of these vectors identified the activator protein 1 (AP-1) binding site as one of the potential sites involved in the quercetin effect. Electromobility shift assay experiments showed that the treatment with quercetin induced the binding of a protein complex to an oligonucleotide containing the AP-1 consensus binding site. This is the first study showing an effect of quercetin on AP-1 activity in thyroid cells. Further studies are in progress to understand the role of AP-1 activation in the effects of quercetin on thyroid function.

In the past few decades, there has been a lot of interest in plant constituents for their antioxidant, anti-inflammatory, anti-microbial and anti-proliferative properties. However, concerns have been raised on their potential toxic effects particularly when consumed at high dose. The anti-thyroid effects of some plant constituents have been known for some time. Indeed, epidemiological observations have shown the causal association between staple food based on brassicaceae or soybeans and the development of goiter and/or hypothyroidism. Herein, we review the main plant constituents that interfere with normal thyroid function such as cyanogenic glucosides, polyphenols, phenolic acids, and alkaloids. In detail, we summarize the in vitro and in vivo studies present in the literature, focusing on the compounds that are more abundant in foods or that are available as dietary supplements. We highlight the mechanism of action of these compounds on thyroid cells by giving a particular emphasis to the experimental studies that can be significant for human health. Furthermore, we reveal that the anti-thyroid effects of these plant constituents are clinically evident only when they are consumed in very large amounts or when their ingestion is associated with other conditions that impair thyroid function.

Quercetin is the most abundant flavonoid present in fruits and vegetables. For its antiproliferative, antiviral, anti-inflammatory and antioxidants activities, it is an active ingredient of several herbal remedies and is available as a nutraceutical. Experimental studies performed in vitro have demonstrated that quercetin inhibits growth and function in normal thyroid cells and may act as a thyroid disruptor. These effects have also been confirmed in vivo using rodent models. Some studies have reported the ability of quercetin to interfere with the metabolism of thyroid hormones, since it inhibits the 5′-deiodinase type 1 (D1) activity in the thyroid, as well as in the liver. Besides the effects on normal thyroid cells, several experiments performed in vitro have shown a potential therapeutic role of quercetin in thyroid cancer. Indeed, quercetin inhibits the growth, the adhesion and the migration of thyroid cancer cells, and it also has redifferentiation properties in some thyroid cancer cell lines. In conclusion, these data suggest that, although its effects can be of benefit in hyperthyroidism and thyroid cancer, caution is required in the use of high doses of quercetin due to its anti-thyroid properties. Further in vivo studies are certainly needed to confirm these hypotheses.

Thyroid cancer (TC) and thyroid autoimmune disorders (AITD) are among the most common diseases in the general population, with higher incidence in women. Chronic inflammation and autoimmunity play a pivotal role in carcinogenesis. Some studies, indeed, have pointed out the presence of AITD as a risk factor for TC, although this issue remains controversial. Prevention of autoimmune disease and cancer is the ultimate goal for clinicians and scientists, but it is not always feasible. Thus, new treatments, that overcome the current barriers to prevention and treatment of TC and AITD are needed. Alkaloids are secondary plant metabolites endowed with several biological activities including anticancer and immunomodulatory properties. In this perspective, alkaloids may represent a promising source of prophylactic and therapeutic agents for TC and AITD. This review encompasses the current published literature on alkaloids effects on TC and AITD, with a specific focus on the pathways involved in TC and AITD development and progression.