**1. Introduction**

Cardiovascular diseases are the number one cause of death in the world [1]. Nowadays, the important role of inflammatory events in cardiovascular diseases is widely known [2]. Systemic inflammation, circulating immune cell activation, and endothelial cell damage are critical events, along with arterial wall damage [3–6]. Furthermore, the relevance of inflammation in the pathogenesis of chronic venous disorder has also been shown [7,8]. Monocytes play a critical role in the inflammatory response [9]. Activated monocytes display relevant immunomodulatory activities, including the secretion of pivotal cytokines, such as pro-inflammatory cytokines interleukin (IL)-6, IL-1β, IL-8, and tumor necrosis factor α (TNF-α). Different mechanisms may be involved in the abnormal activation of monocytes in chronic diseases [10]. There is increasing evidence that gut dysbiosis; increased intestinal permeability, also known as "leaky gut"; and bacterial translocation, are key mechanisms in

the induction of the systemic increase of lipopolysaccharide (LPS) and pro-inflammatory monocyte activation in several chronic diseases [11–13]. LPS is a potent signal for monocyte stimulation [14]. Monocytes have been demonstrated to be involved in the pathogenesis of several cardiovascular diseases, such as atherosclerosis [15].

Flavonoids are the largest group of naturally occurring polyphenolic compounds, present in almost all parts of flowering plants [16]. Their basic chemical structure is made up of two aromatic rings (rings A and B) connected by an oxygen-containing pyran ring (ring C). Flavonoids are classified into different subgroups, including flavones, isoflavones, flavonols, dihydroflavones, flavanes, chalcones, and anthocyanidins, according to the hydroxylation pattern of rings A and B, the oxidative degree of ring C, and the structure and position of the substitutions [17].

The structural diversity of flavonoids results in a wide range of biological effects; the different substitutions on the carbon atoms determine the biological effects of the flavonoids [18]. It has been reported that flavones show different pharmacological actions, such as antinociceptive [19], anti-inflammatory [20], antioxidant [21], antiulcerogenic [22], and anticarcinogenic [23] actions. The combination of multiple pharmacological properties in a single nucleus is quite interesting [16]. Several mechanisms have been shown to be involved in the anti-inflammatory effects of flavonoids. Flavonoids have the ability to modulate macrophages from pro- to anti-inflammatory phenotypes, potentially contributing to the resolution of pre-established inflammatory processes [24,25]. Furthermore, flavonoids have inhibitory effects in platelet activation, being critical cells for vascular inflammation [26].

The therapeutic activity of flavonoids has been suggested for inflammatory diseases such as cardiovascular diseases, obesity, diabetes, bone health, and asthma [27–31]. Furthermore, the potential use of these molecules in the adjuvant treatment of cancer has also been suggested [25,32].

Flavonoids are secondary metabolites in plants, occurring in virtually all plant parts; especially photosynthesizing plant cells [33]. Polyphenols represent the most abundant compounds among secondary metabolites produced by plants. Naringenin, diosmetin, and quercetin are the aglycons of different kinds of flavonoids found in their heteroside form, specifically naringin, diosmin, and rutin. Naringin and its aglycon naringenin are the most important dihydroflavones that have been isolated from citrus fruits [34]. Quercetin and rutin are two flavonols widely distributed among plants and commonly found in daily diets, predominantly in fruits and vegetables [35,36]. On the other hand, diosmin and diosmetin are two flavones found in various dietary sources, such as oregano spice; oregano leaves; citrus fruits; and extracts from specific medicinal herbs of Rosaceae, Asteraceae, Brassicaceae, and Caryophyllaceae [37].

A flavonoid's biological in vivo activity is very dependent on its bioavailability and this is determined by the chemical structure, mainly the type of sugar moiety. In general, the glycoside levels in plasma are low. Deglycosylation occurs both in the small intestine and in the large intestine, depending on the type of sugar moiety and the aglycon produced by the microbiota. Then, metabolites are absorbed via the large intestine and transported into the circulation [38].

It is possible to hypothesize that flavonoids might inhibit the production of pro-inflammatory cytokines through the activation of leukocytes and focusing on those that are mainly secreted by activated monocytes. The aim of this work was to evaluate the immunomodulatory effect of quercetin, rutin, naringenin, naringin, diosmetin, and diosmin on the production of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8 in whole-blood cells stimulated by LPS.
