Potential Role of Dietary Phenolic Compounds in the Prevention and Treatment of Rheumatoid Arthritis: Current Reports

Rheumatoid arthritis (RA) is a complex illness with both hereditary and environmental components. Globally, in 2019, 18 million people had RA. RA is characterized by persistent inflammation of the synovial membrane that lines the joints, cartilage loss, and bone erosion. Phenolic molecules are the most prevalent secondary metabolites in plants, with a diverse spectrum of biological actions that benefit functional meals and nutraceuticals. These compounds have received a lot of attention recently because they have antioxidant, anti-inflammatory, immunomodulatory, and anti-rheumatoid activity by modulating tumor necrosis factor, mitogen-activated protein kinase, nuclear factor kappa-light-chain-enhancer of activated B cells, and c-Jun N-terminal kinases, as well as other preventative properties. This article discusses dietary polyphenols, their pharmacological properties, and innovative delivery technologies for the treatment of RA, with a focus on their possible biological activities. Nonetheless, commercialization of polyphenols may be achievable only after confirming their safety profile and completing successful clinical trials.


Introduction
There exist more than 100 conditions of arthritis known, and among them, rheumatoid arthritis (RA) is one of the most common forms observed in the elderly population [1].RA affects 0.1-2.0% of the population worldwide, being three times more common in the female gender.The condition can begin at any age, although around 80% of all individuals develop the disease between 35 and 50 years old.Their etiology remains poorly understood, and despite recent therapeutic advances, there is no known cure [2].
RA is a systemic autoimmune, chronic, heterogeneous, and inflammatory disease in which the immune system mistakenly attacks healthy cells in the body, reducing quality of life and shortening its duration [3,4].RA is a complex process involving numerous inflammatory mediators and is characterized primarily by aggressive synovial hyperplasia, synovitis, progressive cartilage degeneration, and bone erosion with painful swelling of small joints, fatigue, prolonged stiffness, and fever produced by immune responses and particular innate inflammatory processes [4,5].Although RA affects multiple body systems, the joints of the hands, wrists, feet, ankles, knees, shoulders, and elbows are most often affected [6].The lining of joints becomes inflamed in RA joints, causing joint tissue

Bioavailability and Metabolism of Polyphenols
After daily intake, polyphenols suffer many modifications along the gastrointestinal tract, which greatly influence their nutritional value and consequent health benefits.Therefore, exploring their bioavailability and metabolism is crucial to reveal the full potential of these compounds, of which the majority are considered non-toxic and safe for people [33,34].
Nowadays, it is well-established that polyphenolics are subject to extensive metabolization after consumption, and hence, it is not surprising that absorption is higher than expected, and some of them can be almost totally assimilated.In general, the maximum plasma concentration of polyphenolics is reached 1.5-2 h after ingestion, and excretion rates around 30%, varying between 12 h (flavanols) and 24 h (anthocyanins and hydroxycinnamics) [35,36].
As far as we know, both the bioavailability and metabolism of polyphenol parameters differ significantly between different polyphenol compounds, and sometimes, the most dominant in our diet are not necessarily those that show the highest concentrations of active derivatives in tissues and organs.Indeed, molecular weight, glycosylation and/or acylation and/or polymerization degrees, conjugations, and/or combinations with other molecules impact bioavailability [38].In addition, different pH values also influence these characteristics, as well as solubility, digestibility, the capacity to cross cell membranes, cooking, agronomic practices, food maturity index, and if they are consumed alone, and/or after an overnight fasting and/or accompanied with other foods or alone [39].It is also important to take into account individual genetics, the existence of food intolerances, gender, age, sex, diet, lifestyle, and physiological and/or pathological states, which also interfere with different activities of gut microbiota, enterocytes, related enzymes, and biliary acids, also impact the bioavailability, metabolism and consequent biological effects of these phytochemicals [38].
Figure 1 summarizes the main steps involved in the absorption, metabolism, distribution, and excretion of polyphenols.As expected, and before reaching systemic circulation, there is in the mouth that the degradation of polyphenolics initiates.Here, saliva enzymes remove glycoside groups, and then the compounds reach the stomach, where simpler aglycones, like isoflavones and phenolic acids, such as gallic acid, can be readily absorbed by bilitranslocase (bioac-  [40] and Ray et al. [41]. As expected, and before reaching systemic circulation, there is in the mouth that the degradation of polyphenolics initiates.Here, saliva enzymes remove glycoside groups, and then the compounds reach the stomach, where simpler aglycones, like isoflavones and phenolic acids, such as gallic acid, can be readily absorbed by bilitranslocase (bioaccessibility) or reach intestinal epithelium by passive diffusion thanks to their high lipophilicity or by using active sodium-dependent glucose cotransporters, including glycosides, polymers, and esters, becoming available for absorption [42].On the other hand, the most complex polyphenols go to the small intestine.Here, they suffer glucuronidation, methylation, sulfation, or hydroxylation by cytosolic β-glucosidase and lactase-phlorizin hydrolase enzymes [41].Next, simpler compounds reach the liver via the portal vein and the non-absorbed ones go to the colon to be transformed into simpler units, undergoing decarboxylation, dihydroxylation, demethylation, and/or hydrolysis thanks to the activity of bacterial esterases, including α-rhamnosidases, to suffer a new attempt at absorption by the liver [43].Indeed, evidence reports that most polyphenols are only absorbed after being metabolized in the colon (90.0-95.0%)[44].This event also leads to pH diminution by forming short-chain fatty acids, which, in turn, creates favorable conditions for the proliferation of Actinobacteria, Lactobacilli, and Bifidobacteria probiotic bacteria, hence exerting protective effects against digestive and gastrointestinal disorders, allergies, eczema, and others [38].
Therefore, microbiota causes hydrolysis of glycosidic and ester bonds and cleavage of aglycones into smaller molecules, while hepatocytes produce mainly phase I and II metabolites (conjugates) from intestinal metabolites such as aglycones, phenolic acids, and simple phenols [45].Phase II also occurs in the small intestine and kidneys [46].In addition, the non-absorbed polyphenols in the liver can go again, via bile, to the small intestine to be metabolized again [47].The non-absorbed polyphenols are excreted in urine and feces [47].
Even so, to enhance the absorption, metabolism, and stability of polyphenolics, several strategies have been conducted to improve these topics.Among the most promising ones, nano-encapsulation with biopolymers, chitosan, pectin, whey protein, and liposomal micelle have been hot topics in scientific communities and medicine, pharmaceutical, and other related industries [48,49].

Major Sources of Dietary Polyphenols
Nowadays, the search for more effective, safer, and cheaper bioactive compounds than chemical drugs assumes great importance.Indeed, because most chemical drugs possess several unwanted effects and are little active, many people prefer to use natural molecules [33].Among the most promising molecules, phenolic compounds, including simple phenols (e.g., catechol, pyrogallol, phloroglucinol, and resorcinol) and polyphenols (e.g., coumarins, anthocyanins, lignans, and phenolic acids) seem to be promising therapeutic and/or adjuvant approaches (Figure 2) [50][51][52].Simple phenolics have a low molecular weight, and most of them (except resorcinol) are rapidly absorbed by the human skin, while polyphenols are largely widespread and ubiquitous in nature, being largely found in several types of algae, beans, fruits, bark, herbs and spices, legumes, leaves, nuts, whole grains, oilseeds, and roots (Table 1) [53,54].In a general way, polyphenols can occur in free forms or conjugated with sugar moieties, acids, and other biomolecules that are soluble or insoluble in water, and, of course, these substitutions can interfere with the biological potential of these compounds [55].Indeed, depending on the number and spatial position of hydroxyl groups, they can confer polyphenols with a great capacity to act as electron and hydrogen donors [56].In addition, the CH=CH-COOH group and the double bond found in hydroxycinnamic acids make them more effective in reducing oxidative stress than hydroxybenzoics [57].On the other hand, the presence of an o-diphenolic group and catechol hydroxyl groups, a double bond, and the conjugation between the double bond and the oxo group on the C ring enhance the antioxidant properties of flavonoids [58].It is also important to note the obstruction of the O-methylation at the catechol group can diminish the biological potential of these phytochemicals [59].Noticeably, stilbenes are predominant in grapevines, peanuts, and sorghums (amounts of 0.16-0.77mg per 100 g, 1.8-787.3µg per 100 g, and up 0.01 mg per 100 g, respectively), showing total polyphenol compounds (TPCs) of 9. 3-75.3, 94.4-228.4,and 100-2300 mg GAE per 100 g fresh weight (fw), respectively [60][61][62][63].Lignans are highly present in flaxseeds (amounts of 9 to 30 mg per g, being 75 to 800 times higher than in cereals, fruits, legumes, and vegetables), revealing TPC scores around 3000 mg per 100 g [64,65]; in addition, flaxseeds also present considerable quantities of phenolic acids (800-1000 mg per 100 g) [66].
Focusing on ellagitannins, they were found to be only present in berries from the Rosaceae family, including strawberries and raspberries, rose hip, cloudberries, and sea buckthorn (amounts varying from 21.7 to 83.2 mg/100 g fw) [135].Particularly, punicalagin is predominantly found in pomegranate peels (2803-10,414 mg/100 g) [136].
Of course, quantity values are greatly influenced by genotype, origin, climate, time of harvest, agricultural and processing techniques, and so on [138].

Pharmacological Properties of Dietary Polyphenols
Based on deleterious effects caused by oxidative stress and exacerbated inflammatory responses, it is not surprising that these natural molecules, which are composed of many hydroxyl groups, can easily neutralize radical species or break chains, by giving an electron or hydrogen atom, and interfere with inflammatory pathways, thus contributing to increase immunity defenses and promoting a healthy status.In addition, evidence also shows that they are effective in acting as anti-aging, anti-microbial, and antiproliferative agents and possess abilities to increase insulin sensitivity and digestion, lower blood sugar levels, and ameliorate brain and heart functions.
As expected, their benefits are closely linked to their chemical structure and quantities.Indeed, several studies already reported that, in most cases, an increment in phenolics enhances biological potential [65,75,79,[172][173][174][175][176][177].Therefore, it is not surprising that their interest is increasing worldwide, especially in preventing and/or attenuating several diseases, especially those without medical cures, like AR (Figure 3).In this disease, there is a verified network of inflammatory components, degrading enzymes, angiogenic molecules, and cells.Altogether, this originates immune deregulation, which, without surprise, is not only associated with exacerbated inflammatory responses but also with oxidative stress, affecting particularly the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway (discussed below).Phenolics have shown potential to counteract oxidative stress levels and downregulate exacerbated inflammatory responses, and thus, their use as adjuvant therapy and/or combined with chemical pharmaceutics can be very useful.Similar approaches have been applied in cancer treatment.In fact, in 2019, of the 247 anticancer drugs available, 200 were from natural products while 38 were synthetic drugs and nine were vaccines [33].

Antioxidant Capacity
Reactive oxygen and nitrogen species, namely, superoxide and nitric oxide radicals, play a vital part in the human body, which are signaling molecules that interfere with immune responses and signal transduction pathways, cell growth, and gene expression.However, their overproduction and accumulation, have a negative impact on mitochondria and lead to the formation of more toxic free radical species, such as peroxynitrite and peroxyl radicals, promoting deleterious effects in cells, DNA mutations, disintegration and protein damage of membranes, and alterations in phagocyte-mediated activity, thus playing a pathogenic role in chronic inflammatory diseases.Consequently, inflammation signaling cascades and oxidative stress components are triggered, which in turn enhance the risk of neuropathologies and chronic diseases, such as atherosclerosis, cancer, metabolic syndrome, and, of course, RA [179,180].
Regarding RA, its pathophysiology has been linked to oxidative stress, principally with the Nrf-2 pathway.This is the major pathway involved in the maintenance of homeostatic responses by raising intracellular defense mechanisms and regulating the heme oxygenase-1 axis, controlling macrophage activation and the NF-κB pathway, and reducing stress oxidative and inflammation [181].Under quiescent conditions, Kelch-like ECH-associated protein 1 (Keap 1) holds Nrf2 in the cytoplasm, promoting its ubiquitination and subsequent proteolysis; however, under pathology conditions, Nrf2 is released from Keap1 and enters the nucleus, where the transcription of antioxidant enzymes occurs [182][183][184].
Among the most promising therapeutic and adjuvant approaches, polyphenols assume a prominent interest since they have already been shown to possess notable capabilities to restore oxidative stress and inflammation near basal levels by interacting with Keap1 protein, avoiding its linkage with its binding site in Nrf-2.This subsequently, causes the dissociation of Keap1 from Nrf2, leading to the transcriptional activation of Nrf-2 and, hence, stimulating intracellular antioxidant enzyme (glutathione, catalase, and superoxide dismutase) activity, and, of course, neutralizing oxidative stress [182][183][184].
In general, and in order to establish the antioxidant properties of phenolics, three statements were recently proposed, known as Bors criteria (Figure 4).The first one is the most significant, and it states that because of hydrogen bonding, the presence of a catechol group on the B ring increases the stability of phenolics and, consequently, their antioxidant properties.The second one is the existence of a 2,3 double bond combined with a 4-oxo group on the C ring, which in turn, facilitates electron delocalization and allows for better aryloxyl radical stabilization, while the third one is related to the presence of OH groups at positions 3 and 5 on the A and C rings combined with a 4-oxo group on the C ring, allowing electron delocalization via hydrogen bonds [185].Thus, these characteristics make phenolics capable of acting as electron and hydrogen donors [55,186].Among phenolics, quercetin and myricetin complete all Bors criteria, and hence, they are well-known because of their notable capacity to reduce radicals [187].Moreover, the existence of the catechol group in quercetin and its derivatives enhances their biological potential [185].
Regarding non-flavonoid compounds, hydroxycinnamics showed better antioxidant capacities than hydroxybenzoic acids because of the CH=CH-COOH group, the 7,8-double bond, the carboxyl group with O-alkyl esters, and the presence of hydroxyl groups at the ortho and/or para positions [188][189][190][191].For lignans, it is well-established that their capacity to eliminate radicals and free species is mainly because of the presence of catechol groups [192], while the hydroxylation at position 4 and hydroxyl groups at the ortho position are the main contributors to the antioxidant potential attributed to stilbenes [193].
Compared with flavonoids, these last ones are more effective in eliminating free species and radicals than non-flavonoids, not only because of the presence of more hydroxyl groups but also because of the double bond in positions 2 and 3, the o-diphenolic group and 3 ,4catechol hydroxyl groups on the B ring, and the conjugation between the double-bond and the 4-oxo group on the C ring [191,194].
Even so, it is important not to forget that the catechol and pyrogallol groups also make phenolics vulnerable to autoxidation, particularly when they interact with transition metals; however, the glycosylation and methylation of hydroxyl groups can decline this harmful behavior [195][196][197][198]. Furthermore, pH also influences the antioxidant properties of phenolics; in fact, although lower pH levels increase iron-reducing activity, they diminish iron catalytic activity and chelate activities [199].Regarding non-flavonoid compounds, hydroxycinnamics showed be er antioxidant capacities than hydroxybenzoic acids because of the CH=CH-COOH group, the 7,8-double bond, the carboxyl group with O-alkyl esters, and the presence of hydroxyl groups at the ortho and/or para positions [188][189][190][191].For lignans, it is well-established that their capacity to eliminate radicals and free species is mainly because of the presence of catechol groups [192], while the hydroxylation at position 4 and hydroxyl groups at the ortho position are the main contributors to the antioxidant potential a ributed to stilbenes [193].
Compared with flavonoids, these last ones are more effective in eliminating free species and radicals than non-flavonoids, not only because of the presence of more hydroxyl groups but also because of the double bond in positions 2 and 3, the o-diphenolic group and 3′,4′-catechol hydroxyl groups on the B ring, and the conjugation between the doublebond and the 4-oxo group on the C ring [191,194].
Even so, it is important not to forget that the catechol and pyrogallol groups also make phenolics vulnerable to autoxidation, particularly when they interact with transition metals; however, the glycosylation and methylation of hydroxyl groups can decline this harmful behavior [195][196][197][198]. Furthermore, pH also influences the antioxidant properties of phenolics; in fact, although lower pH levels increase iron-reducing activity, they diminish iron catalytic activity and chelate activities [199].
Focusing on their potential to interact with the Nrf-2 pathway, Diniyah and colleagues [200] revealed that catechin, epicatechin, and gallic acid from non-oilseed legumes present high binding affinities with Keap1, a protein that activates the degradation of Nrf-2, and are therefore promising new Nrf2 activators.Similar results were found involving hesperetin, hesperidin, naringenin, naringin, narirutin, neohesperidin, neohesperidin dihydrochalcone, and nobiletin citrus-derived flavonoids [201] and sesamol isolated from Sesamum indicum L. seed oil [183].Mice treated with 37.5, 75, and 150 mg/kg green tea every 8 h by intragastric administration, which were then sacrificed 4, 12, and 20 h after administration, showed higher levels of antioxidative enzymes and liver phase II enzymes.In addition, docking studies revealed that the most predominant compounds in this tea, which were, caffeine, catechin, catechin gallate, epicatechin, epigallocatechin, epigallocatechin gallate, epicatechin gallate, gallic acid, and gallocatechin, revealed strong Focusing on their potential to interact with the Nrf-2 pathway, Diniyah and colleagues [200] revealed that catechin, epicatechin, and gallic acid from non-oilseed legumes present high binding affinities with Keap1, a protein that activates the degradation of Nrf-2, and are therefore promising new Nrf2 activators.Similar results were found involving hesperetin, hesperidin, naringenin, naringin, narirutin, neohesperidin, neohesperidin dihydrochalcone, and nobiletin citrus-derived flavonoids [201] and sesamol isolated from Sesamum indicum L. seed oil [183].Mice treated with 37.5, 75, and 150 mg/kg green tea every 8 h by intragastric administration, which were then sacrificed 4, 12, and 20 h after administration, showed higher levels of antioxidative enzymes and liver phase II enzymes.In addition, docking studies revealed that the most predominant compounds in this tea, which were, caffeine, catechin, catechin gallate, epicatechin, epigallocatechin, epigallocatechin gallate, epicatechin gallate, gallic acid, and gallocatechin, revealed strong binding affinities with the Keap1 protein [184].In accordance with the mentioned results, the daily intake of 25 mg/kg/body weight (bw) epigallocatechin gallate by rats with lung injury and oxidative stress induced by fluoride displayed the capability to increase antioxidant status and Nrf2 gene expression and reduce inflammatory cytokine [202].Similar results were obtained using endothelial cells pre-treated with polychlorinated biphenyls 126 [203].Furthermore, Li et al. [182] verified that concentrations of apigenin, cyanidin 3-sambubioside, echinacoside, luteolin 5-O-glucoside, quercetin 3-O-rutinoside, and α−tocopherol at 10 and 50 µM can effectively enhance Nrf-2 levels in the nucleus of hydrogen peroxide-induced oxidative-injured rat adrenal pheochromocytoma PC12 cells.It was also demonstrated that 10-100 µM 5-caffeoylquinic acid was a potent Nrf-2 activator in human hepatocellular carcinoma HepG2 cells [204].Finally, Mishra and colleagues revealed that the combination of curcumin (30 mg/kg/bw) with vitamin E (200 mg/kg/bw) could be very effective in counteracting oxidative stress in hypothyroid rats by interfering with NF-κB/AKT/mTOR/KEAP1 [205].
Moreover, positive correlations were already reported between polyphenol amounts and biological potential.Particularly, positive correlations were already reported between sweet cherry anthocyanin-rich fractions and nitric oxide, superoxide radicals (r > 0.9013) [73], and ferric species (r = 0.739) and between TPCs and non-colored and colored fractions from sweet cherry fruits and hydrogen peroxide (r > 0.940) [79].Additionally, a high correlation (r = 0.7581) between honey TPC and the elimination of nitric oxide radicals was also found [180,206], and between total flavonoid amounts in sweet cherry vegetal parts and the inhibition of hemoglobin oxidation (r > 0.9636) [207].

Anti-Inflammatory Abilities
During inflammation, IL-1 and IL-6, tumor necrosis factor (TNF-α), prostaglandins, heat shock proteins, and nitric oxide and superoxide radicals are generated, which, in part, help in controlling this process by activating neutrophils and macrophages [73].Hydrogen peroxide is also released, owing to the activation of nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) kinases and oxidation, hence stopping reactive species accumulation [228,229].However, although inflammatory processes are directly linked to individual development, when these responses are exaggerated, carbohydrate damage, lipid peroxidation protein, and nucleic acid oxidation happen, contributing to the onset of many disorders, including AR [230][231][232].Once again, given that phenolics can counteract oxidative stress and normalize immune responses, it is not surprising that phenolics are a target of extensive research.In fact, they have already been shown to possess capabilities to diminish the activity of COXs, lipoxygenase, and iNOS by interfering with different stages of the inflammatory cascade, namely, by down-regulating NF-κB and activating protein-1 and stimulating Nrf-2, mitogen-activated protein kinase (MAPK), a protein complex responsible for modulating a group of protein kinases that play an essential role in signal transduction by modulating gene transcription in the nucleus, and protein kinase-C [233][234][235][236].In fact, the inhibition of NF-κB is crucial to attenuate inflammatory responses once this complex of proteins is responsible for controlling the expression of many genes involved in inflammation, including IL-1, IL-2, IL-6, and TNF-α, COX-2, vascular endothelial growth factor (VEGF), IL-8, MIP-1α, and MCP-1 chemokines, immunoreceptors, and adhesion molecules.In this way, phenolics can reduce the severity of inflammation [237][238][239].
Catechin and epicatechin (1.7-17.2µM) can also modulate phorbol 12-myristate 13acetate-induced NF-κB activation in Jurkat T cells [254].Particularly, quercetin can inhibit the biosynthesis of leukotrienes in human polymorphonuclear leukocytes and the activation of NF-κB and p38 MAPK in human mast cells by preventing the degradation of Iκ Bα and the nuclear translocation of p65.Hence, it can reduce IL-1β, IL-6, IL-8, and TNF-α expression [255] as well as avoid iNOS gene expression by blocking the activation of IkK kinases, NF-κB, and STAT1 in mouse BV-2 microglia [256].It can also modulate chromatin remodeling by blocking the recruitment of CBP/p300 to the promoters of interferoninducible protein 10 macrophage inflammatory protein-2 genes in primary murine small intestinal epithelial cells [257].On the other hand, kaempferol and galangin display identic properties concerning epicatechin effects in mouse BV-2 microglia [258,259].
Similar to epicatechin, epigallocatechin gallate can also avoid IkK kinase activation, avoiding the degradation of Ik-Bα in culture respiratory epithelial cells and in rat models [260] and blocking DNA binding of NF-κB and hence, diminishing IL-12 p40 and iNOS expression in murine peritoneal macrophages and J774.1 macrophage cells [233,261].Furthermore, 10, 25, 50, and 100 µM epigallocatechin gallate also showed the capacity to attenuate COX-2 expression without affecting COX-1 in colon cancer PC-3 cells [233], as well as the ability to block NF-κB activation in human epithelial cells and reduce iNOS expression and, consequently, nitric oxide radical levels in macrophages at doses of 5 and 10 µM [233].Furthermore, like genistein [262], luteolin can also suppress the activation of NF-κB and the expression of proinflammatory genes and IKK kinases in murine macrophages RAW 264.7 and mouse alveolar macrophages, as well as TNF-α secretion in co-cultured intestinal epithelial Caco-2 and RAW 264.7 cells [263,264].
On the other hand, 25, 50, and 100 µM chebulanim, a natural polyphenol acid isolated from Terminalia chebula Retz inhibited the nuclear translocation of p38 and p65 in liposaccharide-stimulated macrophages in a dose-dependent manner [231].Additionally, aqueous birch leaf extract of Betula pendula Roth inhibits the growth and cell division of inflammatory lymphocytes in a dose-dependent manner because of apoptosis induction [265].
Relative to in vivo studies, the daily ingestion of cherries (141 g) for 10 days by rats and ringdoves downregulated IL-1β and TNF-α pro-inflammatory cytokine levels and raised IL-4 and IL-2 anti-inflammatory cytokines [268].In addition, gingerenone A (10 mg/kg/bw), a polyphenol largely present in ginger, also displayed positive effects in suppressing obesity and adipose tissue inflammation by avoiding macrophage infiltration and enhancing adiponectin, in high-fat diet-fed mice that were treated for 15 weeks [269], as well as quercetin [270].On the other hand, apigenin can stop inflammation in human THP-1-induced macrophages and mouse J 774A, by reducing IL-1β production via inhibiting the activation of caspase-1 through the disruption of NLRP3 inflammasome, as well as diminishing TNF-α and IL-1β thanks to its ability to inactivate NF-κB [241].Apigenin, as well as other polyphenol compounds extracted from chamomile, meadowsweet, and willow bark, including quercetin and salicylic acid (0-100 µM), also revealed the ability to decrease IL-1β, IL-6, and TNF-α in THP-1 macrophages and also protect them against oxidative damage [271].Tannic acid-based nanogel is also an efficient anti-inflammatory agent, showing a notable potential to reduce neutrophil recruitment and pro-inflammatory cytokines, indicating the successful alleviation of inflammation [272].
Moreover, curcumin can easily interfere with NF-κB, as well as with STAT3, thus reducing the expression of TLR-2 and -4 and upregulating peroxisome proliferator-activated receptor , as observed in male rats that were treated with 0.2 µM curcumin for 3 days [273,274].
Among fruits, sweet cherry phenolic-rich fractions can reduce nitric oxide radicals and decrease iNOS and COX-2 expression in RAW macrophages stimulated with lipopolysaccharide [30].Moreover, aqueous and hydroethanolic extracts of their vegetal parts also are effective in inhibiting nitrite levels in a dose-dependent manner in these cell lines [28].Moreover, some Brazilian plants also showed potential to reduce TNF-α and CCL2 levels in lipopolysaccharide-stimulated human monocytic THP-1 cells [275].Regarding individual compounds, ferulic and coumaric acids, which are largely found in Chinese propolis, Lonicera japonica Thunb and Kalanchoe gracilis showed similar capacities [276-278].In addition, 1-1000 µg/mL quince (Cydonia oblonga Miller) peel polyphenols modulated liposaccharide-induced inflammation in human THP-1-derived macrophages, reducing IL-6 and increasing IL-10 expression by inhibiting NF-κB, p38MAPK and Akt pathways [279].
Focusing on clinical trials, it has already been reported that the daily consumption of cherries (280 g) by women can reduce plasma C-reactive protein and nitric oxide radicals 3 h after intake [280].

Anti-Rheumatoid Effects
As expected, polyphenols and polyphenolic-rich sources also reveal promising abilities to attenuate, or even prevent, rheumatoid arthritis, as described in Table 2.

In Vitro Studies
Considering all the previously mentioned results, it is not surprising that polyphenols can be considered promising molecules in preventing and/or attenuating rheumatoid arthritis.
So far, focusing on in vitro assays, it has been already reported that slibinin, a natural flavonoid extracted from milk thistle (Silybum marianum L. Gaertner), shows effectiveness in inhibiting Th17 cell differentiation and inducing macrophage M2 polarization in RAW 264.7 cells; it also promotes apoptotic events and inhibits NF-κB, SIRT1, and autophagy in fibroblast-like synoviocytes at doses of 50, 100, and 200 µM [281].Moreover, 50, 100, and 200 µg/mL oleuropein, the most common polyphenolic detected in olive leaves, showed potential to shift CD4 + T cells from peripheral blood mononuclear cells of RA patients to CD4 + CD25 + FoxP3 Tregs and induce the production of IL-10 and TGF-β [282].In addition, 12.5-50 µg/mL polyphenolic extract from extra virgin olive oil inhibits the inflammatory response in IL-1β-activated synovial fibroblasts, as well as TNF-α, IL-6, COX-2, and microsomal PGE synthase-1 production, thanks to their capability to downregulate the MAPK and NF-κB signaling pathways [283].
Moreover, 5 and 10 µM curcumin showed effectiveness in reducing survivability and decreasing levels of MMP1 and TNF-α in synovial sarcoma SW982 cells, which is considered the best in vitro approach to study RA [284].Additionally, 25-100 µM curcumin was shown to induce apoptosis and inhibit PGE2, by down-regulating anti-apoptotic Bcl-2 and the X-linked inhibitor of the apoptosis protein and upregulating pro-apoptotic Bax expression, in a concentration-dependent manner, on synovial fibroblasts obtained from patients with RA [285].In addition, at 12.5-50 µM, this compound also showed capacity to reduce IL-1β, PMA-induced IL-6, and VEGF-A expression by inhibiting NF-κB and induce dephosphorylation of ERK1/2 and enhance apoptosis in both in MH7A cells and RA-fibroblast-like synoviocytes [286].
Furthermore, 1, 3, and 10 µg/mL resveratrol also showed ability to reduce Sirt1 protein, MMP1 and MMP13 expression [290].In addition at 20 µM, it inhibited the phosphorylation and acetylation of p65, c-Jun, and Fos and reduced binding to the COX-2 promoter, thereby attenuating COX-2 expression in fibroblast-like synoviocytes [291].In addition, at 1-40 µM, this compound also showed an ability to activate Nrf2-2, heme oxygenase-1, and Bcl-2/Bax; induce apoptosis; reduce Keap1 expression and reactive oxygen species and malondialdehyde levels; block NF-κB p6 translocation; inhibit cell proliferation; and migration on fibroblast-like synoviocytes in a dose-dependent manner [292,293].Moreover, Yang and co-workers [294] demonstrated that 25 and 50 µmol/L resveratrol can reduce hypoxia-inducible factor-1α and activate phosphorylation of p38 MAPK and c-Jun N-terminal kinase in IL-1β-stimulated RSC-364 cells, as well as arrest these cells at the G0/G1 cell cycle and enhance their apoptosis.Similar data were reported by Tian et al. [295,296], who also verified that resveratrol can interfere with the PI3K/Akt/BAD signaling pathway, which, consequently, also promotes the inhibition of cells growth and apoptosis.In addition to that, 20 µM resveratrol can also interfere not only with PI3K/AKT but also with the MEK/ERK pathway, and thus induce FOXO transcriptional activity and inhibit cell migration and capillary tube formation in human umbilical vein endothelial cells, preventing angiogenesis [297].On the other hand, Li et al. [298] reported that 50 µM resveratrol can block fibroblast-like synoviocytes in RA cells at the G2/M stage and reduce TNF-α levels and the S phase cell ratio by promoting the serine-threonine kinase-p53 axis, and autophagy, which, subsequently, leads to cells apoptosis.Moreover, 100 and 200 µM resveratrol also showed the ability to reduce the viability of human RA synovial MH7A cells by stimulating H2A.X phosphorylation and consequent apoptosis events, disrupt mitochondrial membrane potentials and stimulat cytochrome c release from the mitochondria to the cytosol, activate caspase-3 and caspase-9 but not caspase-8, upregulate the expression of the NAD-dependent deacetylase sirtuin (SIRT) 1 mRNA and downregulate the expression of the Bcl-X(L) mRNA, hence suppressing synovial cells hyperplasia [299].The capacity of resveratrol to activate caspase-3, and consequently inhibit the proliferation of synoviocytes and induce cell apoptosis in synoviocytes in RA, was already reported by Tiang et al. [300].Furthermore, Wang and colleagues revealed that 25-200 µM of this compound can also reduce mitochondrial reactive oxygen species and Bcl-2-associated X protein (Bax) and increase B-cell-lymphoma-2 (Bcl-2 levels) and apoptotic cells, namely, by regulating the expression of mitochondrial superoxide dismutase [301].On the other hand, a dose of 100 µM resveratrol reduces the expression of MMP-1, MMP-3, MMP-9, RANKL, osteoprotegrin [302], and TNF-α by interfering with the sirtuin1/cortistatin pathway [303], as well as increasing the expression of genes involved in mitosis, the cell cycle, chromosome segregation, and apoptosis in RA fibroblast-like synoviocytes [304].Similar data were obtained by Lu and co-workers [305], who also verified that resveratrol can diminish the expression of IL-1, IL-6, IL-8, and TNF-α and raise the expression of IL-10; in addition, the administration of resveratrol together with 5 µM hydrogen peroxide can induce fibroblast-like synoviocyte apoptosis probably via mitochondrial dysfunction and endoplasmic reticulum stress.Resveratrol can also diminish urban particulate matter-induced COX-2/PGE2 release in human fibroblast-like synoviocytes by inhibiting the activation of NADPH oxidase/ROS/NF-κB [306].Finally, 1, 2, 3, and 5 µM resveratrol can mediated SIRT-1 interactions with p300, modulating RANKL activation of NF-κB signaling, inhibiting osteoclastogenesis, and thus, preventing bone loss in bone-derived cells [307].
In addition, it was also already reported that the combination of 25 µM resveratrol with 0.5 µg/mL methotrexate significantly reduced monocyte chemoattractant protein 1 levels in synovial mononuclear cells from patients with RA [308].

In Vivo Studies
On the other hand, in RA-mice models, 50, 100, and 150 mg/kg/day silibinin showed an ability to diminish IL-1β, IL-6, and TNF-α levels and joint inflammation [281].
Resveratrol was shown to be a promising strategy for attenuating RA in a mice model.In fact, a 12-day treatment with 5 mg/kg, 15 mg/kg, and 45 mg/kg resveratrol can reduce the abnormal proliferation of fibroblast-like synoviocytes, swelling degree of the paw, and malondialdehyde levels and increase superoxide dismutase activity, glutathione peroxidase, and the glutathione reductase ratio [322].Furthermore, at 10 mg/kg, this compound showed an ability to reduce the progression of periodontitis and the rheumatoid factor amount [228], Wnt5a, MAPK3, Src kinase, and STAT3 levels [323], diminish IL-6 and TNF-α levels and atrial apoptosis and fibrosis, and activate the AMPK/PGC-1α pathway [324], as well as decrease the serum rheumatoid factor, MMP-3, cartilage oligomeric matrix protein, IgG, antinuclear antibody, TNF-α, myeloperoxidase, C-reactive protein and malondialde-hyde to about 37,59,44,70,5,30,23,33, and 28%, respectively, and enhance IL-10 and glutathione to about 225 and 273%, respectively, in RA-rats [325].Furthermore, 50 mg/kg resveratrol can diminish paw swelling, TNF-α, IL-1β, TBARs, and NOx, namely, by suppressing NF-κB p65 expression [326], while 10 µMol/kg can reduce inflammatory responses and prevent the loss of matrix proteoglycan content in the cartilage in a rabbit inflammatory arthritis model [327].Moreover, a 10-day treatment with 15 and 20 mg/kg resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function [328].In accordance with other studies, Yang et al. [294] also showed that 400 g/kg/bw resveratrol diminishes oxidative stress and inflammation, by raising serum superoxide dismutase and reducing malonaldehyde, and suppresses the MAPK signaling pathways and angiogenesis in rats with bovine type-II collagen-induced arthritis.Similar results were observed in arthritic rats treated with 5, 50, and 100 mg/kg ellagic acid for 21 days, where ellagic acid also showed a capacity to suppress MTA1/HDAC1-mediated Nur77 deacetylation [310].Furthermore, 25 mg/kg of this compound can also decrease articular edema, NF-κB, and neutrophil elastase, and hence, diminish neutrophil extracellular traps, in RA rats, namely, by interfering with TLR-4, peptidyl arginine deiminase 4 enzyme and COX-2 [336].Resveratrol at 45 mg/kg can also reduce store-operated Ca 2+ entry and enhance the apoptosis in an adjuvant arthritis rat model by targeting the ORAI1-STIM1 complex [329].Additionally, Fernández-Rodríguez et al. [330] reported that 12.5 mg/kg/day resveratrol can also induce the noncanonical autophagy pathway, reduce p62 expression, caspase-3 expression, and poly(ADP-ribose) polymerase, IL-1β, C-reactive protein, and prostaglandin E2, as well as NF-κB synovial tissue expression, which is correlated with p62 expression [330].It can also diminish PCNA, CD68, CD3, monocyte chemoattractant protein-1 staining, cytokineinduced neutrophil chemoattractant-1 and the level of the marker of DNA damage, and 8-oxo-7,8-dihydro-2 -deoxyguanine in RA rats [331].Resveratrol at 2.5 and 10 mg/kg/day can also display an ability to suppress MMP1 and MMP13 amounts in a collagen-induced arthritis rat model [290], while 10 and 50 mg/kg resveratrol can reduce the proliferation of concanavalin A-stimulated spleen cells, articular cartilage degeneration with synovial hyperplasia, and inflammatory cell infiltration, namely, by suppressing the production of COX-2 and PGE2 in adjuvant arthritis rats [332].Resveratrol at 10 mg/kg/day alleviates adjuvant arthritis-interstitial lung disease in rats with induced RA, namely, by preventing the production of pro-inflammatory by modulating the JAK/STAT/RANKL signaling pathway [333], as well as ameliorate fibrosis in rats with induced-RA via the autophagy-lysosome pathway [232].
More recently, to improve resveratrol's bioavailability and effectiveness, it was shown that its combination with methotrexate loaded-nanoemulsion in a transdermal delivery system resulted in a reduction in inflammation by 78.76% and a better anti-arthritic effects [334].Moreover, the nanocarrier QRu-PLGA-DS nanoparticles effectively improved the water solubility and targeting ability of this compound to reverse M1 to M2 type macrophages and ameliorate its anti-inflammatory effects in arthritic rats.In addition, the accumulation of nanoparticles in the lesion area with an exogenous stimulus significantly raises the transformation of M2 type macrophages and decreases the recruitment of M1 type macrophages [335].
Regarding epigallocatechin gallate, 10 mg/kg can ameliorate clinical symptoms and reduce histological scores in arthritic mice, as well as reduce IgG2a antibodies, suppress T cell proliferation and relative frequencies of CD4 T cells, CD8 T cells, and B cell subsets, including marginal zone B cells, T1 and T2 transitional B cells, and increase the frequency of CD4 + -Foxp3 + Treg cells and indoleamine-2,3-dioxygenase expression by CD11b + dendritic cells, NF-κB, Nrf-2, and heme oxygenase-1 [337].On the other hand, in a collagen-induced arthritis rat model, 50 mg/kg/day epigallocatechin gallate also showed the capacity to diminish TNF-α, IL-17, Nrf-2, and malondialdehyde levels and improve heme oxygenase-1, superoxide dismutase, catalase, and glutathione peroxidase levels [234].Moreover, it can also reduce neuroinflammation in RA rats after 2 months of treatment, namely, by activating caspase-3 [338].Moreover, 50 mg/kg epigallocatechin gallate showed the abil-ity to decrease the arthritis index, provide protective effects against joint destruction in mice with collagen-induced arthritis, inhibit osteoclastogenesis and TH17 cell activation, and increase the number of Treg cells [339].On the other hand, the administration of extracellular vesicle-encapsulated epigallocatechin gallate for cartilage repair in rat arthritis downregulated the expression of hypoxia-inducible factor 1-α, inhibited apoptosis of chondrocytes, promoted the recovery of type II collagen, and reduced joint swelling in rheumatoid rats by approximately 39.5% [340].In addition, the nanoindentation of epigallocatechin significantly increased reduced elastic modulus (57.5%), hardness (83.2%), and stiffness (17.6%) in the cartilage of arthritic rats [341].It also showed the capability of preventing cartilage destruction in rats with induced-RA at 10 mg/kg by imbibing myeloperoxidase activity [342].
Regarding green tea, it was also reported that rats with induced RA that ingested 2-12 g/L in drinking water for 1-3 weeks showed significant reductions in RA severity, lower levels of IL-17, and higher levels of IL-10.This is probably due to the capacity of green tea polyphenols to suppress the anti-Bhsp65 antibody response [343].
Furthermore, 150 mg/kg/bw Kalpaamruthaa, a modified indigenous Siddha preparation constituting Semecarpus anacardium nut milk extract, Emblica officinalis, and honey, also showed the potential to reduce oxidative stress, myeloperoxidase, and lipid peroxide and increase the activity of enzymic and non-enzymic antioxidants in arthritic rats [344].
Punicalagin at 50 mg/kg/d also showed the capacity to prevent the translocation of p-65 and avoid the phosphorylation of IkK and Ik Bα by modulating NF-κB pathway in arthritic rats.It also reduced TNFα, IL-6, CD86, CCR7, CD40, and MHC II expression, raised IL-10 expression, and suppressed dendritic cells migration, which, in turn, diminished the differentiation of Th1, Th17, and Th17/Th1-like and promoted the generation of Tregs via the regulation of dendritic cell maturation [288].Syringaldehyde at 10, 25, and 50 mg/kg also showed the ability to alleviate paw and joint edema, reduce TNF-α and IL-6 levels, and increase the level of IL-10 in arthritic rat serum [289].Lower levels of IL-6 and TNF-α were also obtained by Toy and colleagues at doses of 100 mg/kg and 200 mg/kg/bw [345].Furthermore, 50 mg/kg Clitoria ternatea L. flower petals and 2.5 mg/kg of its major compound, which is quercetin-3ß-D-glucoside, showed the ability to reduce MPO activity and lower pro-inflammatory cytokines, chemokines, reactive oxygen and nitrogen species, and TNFR1, TLR2, iNOS, COX-2, and MMP-2 expression levels in rats with RA [346].Similar effects were observed with 150 mg/kg Berberis orthobotrys Bien ex Aitch, which also offered protection against arthritic lesions, oxidative damage, and body weight alterations, ameliorated altered hematological parameters, the rheumatoid factor, and contributed to positively modified radiographic and histopathological changes [347].Furthermore, 250, 500 and 750 mg/kg Diospyros malabarica (Desr.)Kostel fruits also showed the capacity to raise anti-inflammatory enzymes and diminish the anti-inflammatory ones in RA rat model [348].
On the other hand, the daily administration of 100 mg/kg ρ-coumaric acid for 2 weeks showed remarkable capacity to suppress paw edema and body weight loss and curtail cartel [316], age, bone erosion, TNF-α, IL-1β, IL-6, IL-17, and MCP-1 quantities in serum and ankle joints of arthritic rats, as well as the expression of RANKL and TRAP, iNOS and COX-2, JNK, p-JNK, and ERK1/2., namely, by regulating RANKL/OPG imbalance and inhibiting RANKL-induced NFATc-1 and c-Fos expression [238].Similar data were reported by Pragasam and colleagues [349].Focusing on chlorogenic acid, at 10 mg/kg, it can attenuate liposaccharide-induced bone loss based on micro-computed tomography and histologic analysis of femurs from arthritic rats [315].
Theaflavin-3,3 -digallate administrated at 10 mg/kg three times per week for 9 continuous weeks also showed the capability of reducing the expression of IL-1β, TNF-α, and IL-6, as well as MMP-1, MMP-2, and MMP-3 amounts in the synovium of a collagen-induced arthritis mouse model, chiefly by inhibiting the activation of NF-κB and the phosphorylation of P38, JNK2, and ERK [230].Moreover, 50 mg/kg cinnamtannin D1, a polyphenolic compound isolated from Cinnamomum tamala, alleviates the severity of RA, affording reduced clinical scores and paw swelling; reduces inflammatory cell infiltration, cartilage damage in the joints, and IL-17, IL-6, and IL-1β; enhances TGF-β and IL-10 levels; reduces the frequency of Th17 cells; and enhances the frequency of Treg cells, namely by its potential to inhibit aryl hydrocarbon receptor expression and phospho-STAT3/RORγt [350].On the other hand, 200 mg/kg cinnamon barks reduce paw volume, weight loss, and, IL-2, IL-4 and IFNγ in RA mice model [351].
N-feruloylserotonin, a natural polyphenol that belongs to indole hydroxycinnamic acid amides, administered at 3 mg/kg/day orally reduced C-reactive protein in plasma and the activity of LOX in the liver rats.It also reduced mRNA transcription of TNF-α and iNOS in the liver and IL-1β in plasma and IL-1β mRNA expression in the liver and spleen of arthritic rats [352].
In addition, 50, 100, and 400 mg/kg mangiferin inhibits mRNA expression of cytokine genes in the thymus and spleen of mice with induced-arthritis and lead to decreased serum levels of IL-1β, IL-6, TNF-α, and RANKL by downregulating NF-κB and activating ERK1/2 [355].
Sarcococca saligna plant at 250 mg/kg also showed ability to diminish IL-1β, IL-6, COX-2, prostaglandin E2, TNF-α and NF-κB levels, and the arthritic index and paw inflammation and enhance the expression of IL-4 and IL-10 [236].On the other hand, 10 mg/kg curcumin showed similar effects as the methotrexate (0.5 mg/kg) positive control in reducing TNF-α and IL-1β in both the synovial fluid and blood serum of arthritic rats [356].Aqueous extracts of Dichrostachys cinerea Wight et Arn.fruits at doses of 150.96 mg GAE/g and 75.48 mg GAE/g reduced IL-1β, IL-6, TNF-α, and cortisol levels, lipid peroxidation, and NOx production [357].In addition, 170-1350 mg/kg of the Circaea mollis Sieb.and Zucc.plant can also reduce paw and inflammatory swelling, the arthritis index, and TNF-α and IL-1β and increase the production of serum IL-10 in Freund's complete adjuvant-induced arthritis model in rats [358].Opuntia littoralis at 10 and 20 mg/100 g bw also revealed the potential to reduce joint inflammation, paw swelling, edema, MDA, and IL-1β, IL-6R, IL-6, IL-17, and IL-23 and ameliorated COX-2, NF-κB, STAT-3, PTEN, and RANKL expression, namely, by upregulating the expression of miR-28 and miR-199a [239].Furthermore, 25 and 100 mg/kg Antrocaryon micraster A. Chev.and Guillaumin seed extract also showed capacity to diminish cachexia, paw edema, infiltration of inflammatory cells, pannus formation, and synovium damage in rats with induced RA [359].Moreover, the addition of 20% dried plums into the normal diet of transgenic mice with induced-RA showed notable protective effects in protecting articular cartilage, reducing synovitis, IL-1β, MCP1, MIP1α, MMP1, and MPP3, and RANKL expression and repressing TNF-induced formation of osteoclasts and mRNA levels of cathepsin K and MMP9 by inhibiting nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) expression, and NF-κB activation [360].On the other hand, 750 mg/kg Opuntia monacantha showed effectiveness in reducing paw edema, the arthritic score, the rheumatoid factor, inflammation, COX-2, IL-6, TNF-α, IL-1, NF-κB, bone erosion, and pannus formation, restoring hemoglobin, white blood count, and platelet parameters, increasing catalase and superoxide dismutase levels, and enhancing IL-4 and IL-10, namely, by its potential to inhibit glutaminase 1 activity in a RA rat model [361].In addition, 800 mg/kg Solanum nigrum also showed effectiveness in reducing paw edem, and restoring body weight, hematologic parameters, and radiographic and histopathologic alterations towards normal in different RA rat models [362].
In addition, 15 mg/kg quercetin and 10 and 20 mg/kg quercetin-loaded chitosan showed the capacity to reduce TNF-α and IL-6, as it was observed that the nanoencapsulation of quercetin is an added value to improve its efficacy in rats with induced RA [363].In another study, 1.25 g/kg grape polyphenols mixed with 1.25 g/kg propolis showed potential to diminish the intensity of cachexia and alleviate RA scores in RA female rats [364].Reduced cachexia and arthritic paw scores were also reported by Decendit [150], who treated chronic rat adjuvant-induced arthritis with 125 mg/kg malvidin 3-O-β glucoside.
Phoenix dactylifera L. seeds can diminish IL-1β levels, paw edema, the erythrocyte sedimentation rate, and C-reactive protein in rats [365].

Clinical Trials
Regarding clinical trials, it was found that 500 mL/day of low-calorie cranberry juice is able to attenuate RA symptoms in women with this disease after a 90-day treatment by decreasing anti-cyclic citrullinated peptide antibodies levels, pain intensity, and swollen joints; however, no inflammatory biomarkers were verified [366].Additionally, the daily ingestion of 500 mL/day of low-calorie cranberry juice with 3 g of fish oil ω-3 fatty acids showed effectiveness in C-reactive protein, the erythrocyte sedimentation rate, and relatedpain [367].On the other hand, pomegranate extract (250 mg for 8 weeks), in addition to alleviating swollen, pain intensity, and tender joints in patients with, can also diminish the erythrocyte sedimentation rate and morning stiffness and enhance glutathione peroxidase.No alterations were found in CRP, MDA, or MMP3 levels [368].Finally, a 1 g daily dose of resveratrol for 3 months [369] also showed effectiveness in reducing joint swelling and tenderness, as well as TNF-α, IL-6, protein C-reactive, MMP-3, the erythrocyte sedimentation rate, and undercarboxylated osteocalcin in patients with RA of both genders [369].

Conclusions
In general, the present review provides evidence that supports the therapeutic effect of polyphenols.Polyphenols are largley present in nature and seem to be a promising approach to the boost immune system and contribute to a healthy status.Contrary to chemical pharmaceutics that originate several side effects and their loss of efficacy over time, it is largely belief that phenolics are more effective and a safer option.This is mainly due to their capacity to counteract oxidative stress and interact with inflammatory pathways.In this way, it is not surprising that their use as an adjuvant to conventional antirheumatic drugs is considered an added value.However, although phenolics are easy to obtain and economical, most of them present poor bioavailability and stability and rapid metabolism.Therefore, their encapsulation is beneficial to increase their efficacy.In addition, their safety profile and clinical trials need to be more explored.

Figure 1 .
Figure 1.Summary of polyphenol absorption, distribution, metabolism, and excretion in different segments of the gastrointestinal tract (adapted Olivero-David and co-workers [40] and Ray et al. [41].

Figure 4 .
Figure 4. Representation of phenolic antioxidant abilities explained by Bors criteria, involving their structure.Bors 1: catechol group on the B ring (green); Bors 2: 4-oxo group and 2,3 double bond on the C ring (blue); Bors 3: hydroxyl (OH) groups at the 3 and 5 groups on the A and C rings combined with a 4-oxo group on the C ring (adapted from Pla er and co-workers [185] and created with ChemDraw Professional 16.0 (CambridgeSoft, Perkin Elmer Inc., Waltham, MA, USA)).

Figure 4 .
Figure 4. Representation of phenolic antioxidant abilities explained by Bors criteria, involving their structure.Bors 1: catechol group on the B ring (green); Bors 2: 4-oxo group and 2,3 double bond on the C ring (blue); Bors 3: hydroxyl (OH) groups at the 3 and 5 groups on the A and C rings combined with a 4-oxo group on the C ring (adapted from Platzer and co-workers [185] and created with ChemDraw Professional 16.0 (CambridgeSoft, Perkin Elmer Inc., Waltham, MA, USA)).

Table 1 .
Main polyphenols found in nature and their phenolic-rich sources.

Table 2 .
Main effects attributed to polyphenolic exposition and daily treatment.