Flavonoids, including around 6000 phenolic compounds, are products of the secondary
metabolism of plants which can be a part of one’s diet via the consumption of many
edible plants. Flavonoids can be classified into flavonols (such as quercetin, kaempferol,
isoquercetin, etc., found in onions, apples, berries, kale, leeks, broccoli, blueberries,
red wine and tea), flavones (such as glycosides of luteolin, chrysin and apigenin,
commonly found in fruit skins, parsley and celery), isoflavones (such as genistein,
daidzein and glycitein present in leguminous plants, mainly soy and soy products),
flavanones (such as naringenin, eriodictyol and hesperidin exclusive of citrus fruits),
flavanols (such as epicatechin, catechin, gallocatechin, epigallocatechin, epigallocatechin
gallate and also polymeric forms or condensed tannins as found in cocoa and tea),
and anthocyanidins (such as pelargonidin, cyanidin and malvidin, found in red wine
and berry fruits). Chemically, flavonoids have a polyphenolic structure that confers
antioxidant activities on them. The antioxidant properties of flavonoids have been
recognized since for more than 40 years ago [1] and, in that time (1976–2016) nearly
23,000 publications have appeared (more than 20,000 research articles and 2600 reviews)
according to research in the Scopus database (searching ‘flavonoid and antioxidant’).
However, flavonoid biological activities go beyond antioxidant properties, although
some of them are related to these abilities. Some particular kinds of flavonoids have
shown protective effects against cancer [2,3], cardiovascular diseases [4,5,6], gastrointestinal
alterations [7] and nervous system-related syndromes, such as depression [8], epilepsy
[9,10], Alzheimer’s disease [11] and neurodegenerative disease [12], among other pathologic
conditions.
The anti-inflammatory actions of particular flavonoids have also appeared in recent
years. The evidence in the literature is based on in vitro and in vivo studies as
well as on clinical studies. In an inflammation context, some of the flavonoids’ action
mechanisms, such as acting as antioxidants, modulating gene expression (i.e., cytokines,
adhesion molecules) or enzyme activities, have been described. However, the role of
flavonoids in the specific arm of the immune response still remains quite unexplored.
The Special Issue of Nutrients entitled, ‘Flavonoids, Inflammation and Immune System’
aimed to encourage researchers to update the knowledge of these compounds from these
two, closely related, biological aspects: inflammatory response, mainly conducted
by macrophages and neutrophils as an expression of the innate immune system activation;
and the immune system concerning, above all, acquired immunity. As a result, this
Special Issue contains examples of the interest in these areas worldwide. The articles
included here demonstrate the tendency for researchers to explore flavonoids, either
as a pure compound or included in food and their impact on cells, animals or humans
in reference to inflammatory or immune response. This issue provides an opportunity
to update current knowledge about some examples of the six subclasses of the flavonoid
compounds and their effects—even at molecular level—on immunity and inflammation,
but also in inflammatory-mediated diseases such as insulin-resistance obesity, cardiovascular
disease and even in cancer. The Special Issue contains six review papers [13,14,15,16,17,18]
and eight research papers [19,20,21,22,23,24,25,26] on the current knowledge in the
field. Contributions are from countries in Africa (South Africa), America (Brazil),
Asia (China, Korea, Japan and Taiwan) and Europe (Germany, Spain and Switzerland).
The review by Vezza et al. [13] focuses on the effect of flavonoids on inflammatory
bowel disease, going in depth into the proposed action mechanisms. These authors report
in vitro and in vivo studies about the effect of anthocyanins, chalcones, flavanones,
flavones, flavonols, flavanols and isoflavones on inflammatory bowel disease, and
they also disclose the lack of clinical trials to confirm the actual role of flavonoids
in this inflammatory disease [13]. The review by Goya et al. [14] also includes some
of the studies of an important source of flavanols—cocoa—on animal models of colon
inflammation. On the other hand, quercetin, a flavonol with long-recognized unique
biological properties, is also the focus of a review article by Li et al. [17], who
provide a review of the literature about the effects and mechanisms of quercetin on
inflammation and immune function in in vitro, in vivo and in clinical studies. Overall,
the majority of the literature revised supports the benefits of prolonged supplementation
with quercetin. As an example of the varieties of mechanisms of quercetin’s action,
a research article in the issue looks in depth at the ability of this flavonol to
modulate the sealing of epithelial cells through tight junction gene expression regulation
by microRNAs [25]. Another flavonol with well-known biological activities is myricetin.
Semwal et al. [18] provide an extensive review of the studies demonstrating, among
others, its anti-oxidant, anti-photoaging, anti-cancer, anti-platelet aggregation,
anti-hypertensive, anti-inflammatory and immunomodulatory and anti-allergic activities
and applications. They conclude that, although more toxicity studies should be developed,
myricetin may constitute a new agent for these situations in the near future.
The Special Issue contains only one in vitro study showing that one flavonol—kaempherol—is
able to partially inhibit stress-induced inflammation and hepatic insulin resistance
in HepG2 cells [23]. On the other hand, although it is well established that the principal
pharmacological action of phlorizin, a chalcone, is to produce renal glycosuria and
to block intestinal glucose absorption through inhibition of the renal and mucosal
sodium–glucose symporters, one article included in this issue highlights other complementary
effects using an in vivo approach in obese mice, such as its action on hepatic steatosis,
inflammation and fibrosis [26].
Cocoa, as a food relatively rich in flavonoids, is the focus of several articles in
this issue. There are two reviews that compile studies demonstrating the anti-inflammatory
action of cocoa consumption. Goya et al. [14] focus on inflammation as a pathogenic
mechanism involved in cardiovascular disease and they compile in vitro studies as
well as approaches in experimental animals showing its particular effect on inflammation
markers. Moreover, they comment on the most recent publications on the effects of
cocoa on anti-inflammatory markers in human cohorts. In this context, the critical
review by Ellinger et al. [15], who include 33 randomized, controlled trials reporting
the effects of cocoa consumption on inflammatory biomarkers, is important. Nevertheless,
these authors conclude that the evidence for the anti-inflammatory effects of cocoa
is currently scarce, although cocoa consumption may prevent or even reduce vascular
inflammation. Staying with the effects of cocoa and chocolate, this Special Issue
also includes a research article [21] focused on a cross-over, placebo-controlled,
double-blind, randomized clinical trial conducted in 92 patients infected with human
immunodeficiency virus (HIV)—a population with a high cardiovascular risk. This study
also includes another food rich in polyphenols—yerba mate. The conclusion of this
first clinical study to evaluate the effect of those flavonoids on the inflammatory
profile of such patients undergoing antiretroviral therapy, indicates that 65 g dark
chocolate is able to increase high-density lipoprotein cholesterol (HDL-c) concentrations
[21]. A different effect of cocoa is shown by Camps-Bossacoma et al. [22], who reported
the tolerogenic effects of cocoa on a rat model of oral sensitization. This study,
focused on acquired immunity, reveals the changes produced by cocoa intake on mesenteric
lymph nodes, which eventually prevent oral immunization to a food allergen. Gut-associated
lymphoid tissue is also evaluated in the study by Martín-Peláez et al. [20], who included
a clinical trial with olive oil phenolic compounds. This randomized, controlled, double-blind,
cross-over human trial demonstrates that the consumption of a virgin olive oil containing
500 mg/kg olive oil phenolic compounds increases the proportion of intestinal bacterial
coated to IgA [20]. Another clinical study (open, prospective, randomized, cross-over,
controlled feeding trial) includes the effect of tomato and olive oil on cardiovascular
disease risk factors [19]. This article reports that a single tomato intake, especially
tomato sauce enriched with refined olive oil, decreases plasma total cholesterol,
triglycerides and several cellular and plasma inflammatory biomarkers, whereas it
increases HDL-c concentration.
On the other hand, although some extracts are not sufficiently characterized in order
to precisely know the flavonoid pattern present, they have been shown to be effective
on several inflammatory disorders. This is the case for the extract of Zingiber zerumber,
very rich in flavonoids and with significant protective effects on retinal inflammation
[24].
Finally, it has to be taken into account that, despite the increasing reports about
the benefits of flavonoids on inflammation, knowledge about their potential health
risks is also provided. In this issue, Yu et al. [16] examine the anti-inflammatory
benefits of isoflavones, but also review the current evidence of their negative health
effects.
We hope that the articles contained within this issue, but also the references they
include and comment on, are of interest to researchers, clinicians, dieticians and
the rest of professionals or non-professionals involved in the passionate world of
the interaction between diet—particularly those with food rich in flavonoids—and health.
Besides the update in the knowledge about the particular actions of flavonoids on
immunity and inflammation, we also encourage further clinical trials and experimental
research to characterize intracellular action mechanisms, to establish the amount
of flavonoids needed to achieve such effects and also to establish the precise action
of each particular flavonoid or extract containing flavonoids.