
==== Front
Int J Mol SciInt J Mol SciijmsInternational Journal of Molecular Sciences1422-0067MDPI 10.3390/ijms17060921ijms-17-00921ReviewFlavonoids as Cytokine Modulators: A Possible Therapy for Inflammation-Related Diseases Leyva-López Nayely 1Gutierrez-Grijalva Erick P. 1Ambriz-Perez Dulce L. 2Heredia J. Basilio 1*Segura-Carretero Antonio Academic EditorGómez Caravaca Ana Maria Academic Editor1 Centro de Investigación en Alimentación y Desarrollo A.C., Carretera a Eldorado Km 5.5 Col. El Diez, 80110 Culiacán, Sinaloa, Mexico; medinajames@example.org (N.L.-L.); medinajames@example.org (E.P.G.-G.)2 Universidad Politécnica del Mar y la Sierra, Carretera a Potrerillos del Norote/La Cruz Km 3, La Cruz, 82740 Elota, Sinaloa, Mexico; medinajames@example.org* Correspondence: medinajames@example.org; Tel.: +52-166-776-0553609 6 2016 6 2016 17 6 92130 4 2016 03 6 2016 © 2016 by the authors; licensee MDPI, Basel, Switzerland.2016This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).High levels of cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6, are associated with chronic diseases like rheumatoid arthritis, asthma, atherosclerosis, Alzheimer's disease and cancer; therefore cytokine inhibition might be an important target for the treatment of these diseases. Most drugs used to alleviate some inflammation-related symptoms act by inhibiting cyclooxygenases activity or by blocking cytokine receptors. Nevertheless, these drugs have secondary effects when used on a long-term basis. It has been mentioned that flavonoids, namely quercetin, apigenin and luteolin, reduce cytokine expression and secretion. In this regard, flavonoids may have therapeutical potential in the treatment of inflammation-related diseases as cytokine modulators. This review is focused on current research about the effect of flavonoids on cytokine modulation and the description of the way these compounds exert their effect.

flavonoidsanti-inflammatory effectcytokine inhibition
==== Body
1. Introduction
Flavonoids are natural occurring compounds with a wide range of molecular diversity, and more than 10,000 structures have been reported [1]. Fruits, vegetables, herbs and other plant food are all flavonoid sources [2]. The interest in flavonoids has arisen because the intake of these compounds has been associated with the prevention and treatment of diseases, which is translated to benefits in health [2,3,4]. The anti-inflammatory effect of flavonoids is one important biological activity.

The activity of flavonoids in the inflammatory response include the inhibition of inflammatory mediators like reactive oxygen species (ROS) and nitric oxide (NO); the regulation of activity of inflammatory enzymes, such as cyclooxygenases (COXs) and inducible nitric oxide synthase (iNOS); the reduction in levels of production and expression of cytokines and the modulation of transcription factors, such as the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and activating protein-1 (AP-1) [5,6,7,8]. When the inflammatory response is not regulated, it results in an increase in the concentration of inflammatory mediators, which might lead to the occurrence of several chronic diseases, namely rheumatoid arthritis, coronary diseases and cancer, among others [9,10]. There is evidence to suggest that inflammatory cytokines have potential as therapeutic targets to treat inflammatory diseases [11], therefore, studying the effect of flavonoids on inflammatory mediators, especially by modulating cytokines, is relevant in order to develop alternative treatments for inflammation-related diseases.

The present manuscript will review recent evidence regarding the role of flavonoids as modulators of inflammatory mediators, mainly cytokines, associated with the inflammatory response.

2. Inflammatory Response
Inflammation is a response of the organism to the presence of diverse agents, such as pathogens (bacteria, fungi and viruses), trauma (shock or burns), toxic compounds (pollutants), as well as reactions of the immune system (hypersensitivity) in the body, which causes a disruption of tissue homeostasis [12,13]. There are two types of inflammation, acute or chronic. The former is the initial response to injury and lasts a few hours or a few days. When acute inflammation does not successfully eliminate damaging agents it can cause a chronic phase. Chronic inflammation is an extended inflammation period (weeks to months) and is associated with the presence of lymphocytes and macrophages, vascular proliferation, fibrosis and tissue destruction. Moreover, chronic inflammation has been related to diseases, such as rheumatoid arthritis, asthma, atherosclerosis, Alzheimer's disease and cancer, among others [14,15,16].

During inflammation, cells of the immune system, mainly macrophages, could be activated through the recognition of a pathogen endotoxin, lipopolysaccharide (LPS), by Toll-like receptors (TLR). This event provokes a signaling pathway that will release the NF-κB, that activates genes associated with the transcription of proteins related to the inflammatory process, such as iNOS, responsible for NO synthesis, COXs, which synthetize prostaglandins, and cytokines. The TLR signaling pathway also triggers the generation of ROS [14,17,18,19]. Activating protein-1 (AP-1) is another transcription factor that is important during the inflammatory response. This factor responds to a wide variety of stimuli such as bacterial and virus infection, stress and growth factors leading to the regulation of gene expression of pro-inflammatory mediators, including cytokines [20]. Overproduction of some inflammatory mediators, such as cytokines, as a result of chronic inflammation, might lead to the occurrence of several chronic diseases [21,22,23].

3. Cytokines
Cytokines are proteins that play an important role in the inflammatory response. The majority of the cytokines are produced by activated lymphocytes and macrophages, although endothelial and epithelial cells are able to produce these proteins, too. Cytokine expression is regulated by NF-κB and AP-1 and may be triggered by LPS, ROS and microbial species, among others [24]. Interleukin (IL)-1β and tumor necrosis factor (TNF)-α are two of the main cytokines involved in the inflammatory response. Briefly, these cytokines induce the expression of adherence molecules in endothelial tissue; participate in the synthesis of other cytokines, namely IL-6, and chemokines (IL-8 and monocyte chemoattractant protein-1 (MCP-1)), growth factors, eicosanoids and NO [14]. Other relevant cytokines are IL-10 (anti-inflammatory cytokine), IL-4 and IL-3, which together downregulate pro-inflammatory signals [6,25].

Cytokines can be classified into two groups: those related to acute inflammation and those responsible for chronic inflammation [26]. The cytokines involved in acute inflammation are IL-1, TNF, IL-6, IL-11, IL-8, IL-16 and IL-17, among others, whereas cytokines related to chronic inflammation are those mediating humoral responses, like IL-4, IL-5, IL-6, IL-7 and IL-13; additionally, there are cellular responses, namely IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10 and IL-12, interferons (IFN), transforming growth factor (TGF)-β and TNF-α [26].

It has been proposed that a prolonged overproduction of inflammatory cytokines without regulation might lead to incidence of chronic diseases, such as, rheumatoid arthritis, atherosclerosis and Alzheimer's disease, among others [15,16,27]. So the study of these proteins as biomarkers in inflammation-related diseases is of relevance to determine adequate treatment.

Cytokines as Biomarkes in Inflammation-Related Diseases
Of all the cytokines associated to chronic inflammation that were mentioned before, this review will focus on IL-1β, TNF-α and IL-6, due to the fact that these are the most well-studied and have a predominant role in chronic inflammation-related diseases. Among the chronic inflammation-related diseases that have shown to be associated to these cytokines are: rheumatoid arthritis; atherosclerosis; metabolic syndrome and associated type 2 diabetes; neurodegenerative disorders such as Alzheimer's disease, and; some forms of cancer in which inflammatory reactions promote tumor development [28]. Experimental research has linked cytokines IL-1β, TNF-α and IL-6 with several chronic inflammation-related diseases. For example, in Alzheimer's disease, the inflammatory response in neurons includes activation of microglia (cells that protect neuronal function), astrocytes, macrophages and lymphocytes, resulting in the release of cytokines and other inflammatory mediators [29,30]. The release of these inflammatory mediators leads to the further release of more inflammatory factors, as well as the recruitment of monocytes. In this sense, the inflammatory response contributes to the progress of Alzheimer's disease accelerating the course of the disease. When microglia are activated, it results in an increased secretion of pro-inflammatory cytokines like IL-1β, IL-6 and TNF-α, thereby enhancing the ability of monocytes to pass through the blood-brain barrier [29,30].

IL-6, along with its receptor sIL-6Ralfa, commands the change from acute to chronic inflammation by shifting the nature of leucocyte infiltrate from polymorphonuclear neutrophils to monocyte/macrophages [31]. Because of the latter, IL-6 is known to be associated with chronic inflammation and related diseases. For example, elevated serum IL-6 levels have been detected in patients with systemic cancers, rheumatoid arthritis, systemic lupus erythematosus, psoriasis and Crohn's disease as compared to healthy controls or patients with benign diseases [32,33,34,35,36]. It has been demonstrated that IL-6 is secreted by many types of cancer cells as it occurs in renal cell carcinoma. IL-6 is abundant in the serum of 50% of the patients with metastatic renal cell cancer; moreover, these cancer cells have shown the production of IL-6 and expression of IL-6 mRNA and of the soluble and membrane-bound gp120 chain of the IL-6 receptor [37,38]. This has turned IL-6 into a drug target in the treatment of chronic inflammatory diseases [26,31], since the inhibition of IL-6 and its signaling cascade was effective as treatment regimen in studies of inflammatory diseases [31,34,39,40].

IL-1β, in conjunction with other inflammatory mediators, has shown to be induced by the activation of microglia cells, which can lead to neuronal death, and thus to the progression of Alzheimer's disease [29,30,41]. Additionally, higher levels of serum IL-1β have been found in patients with abdominal obesity and periodontitis [42]. Another example of the role of cytokines in chronic diseases can be found between TNF-α and rheumatoid arthritis, where anti-TNF-α antibodies were added to in vitro cultures of cells from diseased joints and inhibited the production of IL-1β and other cytokines. Additionally, the use of TNF-α inhibitors has demonstrated remarkable efficacy in the control of diseases' signs and symptoms [43]. Moreover, in Alzheimer's disease, during amyloid beta-peptide aggregation, microglia cells are activated and thus the production of TNF-α is stimulated, promoting neuronal death [29,41,44]. IL-1β and TNF-α are produced by activated macrophages, as well as mast cells, endothelial cells, and some other cell types. The principal role of these cytokines in inflammation is in endothelial activation. Both IL-1β and TNF-α stimulate the expression of adhesion molecules on endothelial cells. This increases leukocyte binding and recruitment, and enhance the production of additional cytokines and eicosanoids. TNF-α also increases tissue fibroblasts, resulting in increased proliferation and production of extracellular matrix [14,43,45].

Because of the important role of cytokines, and other inflammatory mediators, in the development of diseases like rheumatoid arthritis and cancer, there have been efforts looking for pharmaceutical drugs to treat inflammation-related diseases.

4. Anti-Inflammatory Drugs
There are two main types of anti-inflammatory drugs: the nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX activity, and cytokine receptor inhibitors, which block cytokine activity. Examples and the mode of action of these anti-inflammatory drugs will be mentioned next.

4.1. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed and come in different chemical groupings [46,47]. It has been reported that all the NSAIDs drugs act by inhibiting COX enzymes, which are involved in inflammation and are responsible for the synthesis of prostaglandins involved in normal physiological processes. The inhibition of these actions is responsible for the majority of the adverse effects of NSAIDs in clinical use, and for their main toxicity and overdose [46,48]. All NSAIDs have been reported to increase the risk of gastrointestinal damage; the most common side effects range from benign dyspepsia and esophagitis to upper-gastrointestinal bleeding, perforation, and gastric outlet obstruction [49,50,51].

4.2. Cytokine Receptor Inhibitors
The cytokine receptor inhibitors are drugs based on the premise that, in order to function, cytokines must bind to specific receptors. Some cytokines have one receptor chain, like type I interferons, whilst other cytokines bind to shared receptors, like IL-4 and IL-13. In this sense, the mechanism of action of cytokine receptors is not yet well understood, although it is thought that receptors are pre-assembled on the cell surface and are activated by structural changes in the receptors upon binding [52,53,54,55].

On this subject, several drugs have been developed to inhibit cytokine activity. These include the inhibitors of TNF-α and IL-1β with different modes of action [55]. For example, Etanercept, Infliximab and Anakinra are drugs that bind to TNF-α and IL-1 receptors, respectively [52,55].

Moreover, in the treatment of rheumatoid arthritis, several drugs have been used; among the most common are the biologic disease-modifying antirheumatic drugs (bDMARD) or TNF-α inhibitors. However, even with these drugs, around 20%–40% of patients have shown an inadequate response. An alternative is the use of Tocilizumab, a humanized anti-IL-6R monoclonal antibody that prevents IL-6 from binding to its receptor IL-6R [56,57,58,59]. Some other drugs have been studied with the purpose of blocking cytokine actions, and some of these are summarized in Table 1 [60].

Due to its importance in the progression of chronic inflammatory diseases, the control of cytokine action is still a major focus of drug and pharmaceutical research. With efforts in developing cytokine antagonists like cytokine receptor blockers, it is worthwhile to mention that cytokine receptor inhibitors have secondary effects. For example, when Tocilizumab, an anti-IL-6 receptor widely used in the treatment of rheumatoid arthritis, is used in combination with disease-modifying antirheumatic drugs, an elevation in cholesterol and alanine aminotransferase levels have been reported [61]. On the other hand, Anakinra has not shown any adverse effects when used in patients with acute gouty arthritis, while some other therapeutic agents such as Ustekinumab, Etanercept and daclizumab have proven not to be effective against multiple sclerosis [62].

Due to secondary effects that occur when using anti-inflammatory drugs on a long-term basis, it is primordial to find alternative therapies to treat inflammatory diseases. Natural compounds, such as flavonoids, are among the studied molecules in alternative research treatment for inflammation-related illness.

5. Flavonoids and Their Anti-Inflammatory Properties
Flavonoids are natural compounds with a common C6–C3–C6 structure containing two aromatic rings linked by a three carbon chain, typically organized as an oxygenated heterocyclic ring (Figure 1) [70]. The main classes of flavonoids are flavonols, flavones, flavanones, flavanols, isoflavones and anthocyanidins [71]. These compounds are produced as secondary metabolites by plants as defense mechanism against biotic and abiotic stress conditions, mainly [70]. Furthermore, it has been extensively demonstrated that flavonoids possess a wide range of health benefits due to their nutraceutical properties such as antibacterial, antioxidant and anti-inflammatory, among others [8,72,73]. The anti-inflammatory potential of flavonoids is of particular interest for the purpose of this review.

It has been well established that flavonoids have a similar mechanism of action to NSAIDs. In addition, flavonoids inhibit the activity or gene expression of other pro-inflammatory mediators aside from COX. Indeed, flavonoids can up/down regulate transcriptional factors in inflammatory and antioxidant pathways, like NF-κB and Nrf-2 [74].

In this regard, polyphenols presented anti-inflammatory activity in LPS-induced inflammation in RAW 264.7 macrophage cells. Flavonols from C. ternatea exhibited a strong suppression of COX-2 activity and partial ROS inhibition, while its ternatin anthocyanins inhibited nuclear NF-κB translocation, iNOS protein expression, and NO production [75]. Flavonoids, such as apigenin, genistein, and luteolin glycosides from J. platyphylla, an endemic plant from Mexico, showed potential as anti-inflammatory agents due to their significant inhibitory effects on ROS and NO levels produced by LPS-induced inflammation in RAW 264.7 mouse macrophage cells. The authors proposed a hypothetical mode by which flavonoids exert their anti-inflammatory role (Figure 2) [76]. Extracts from three Mexican oregano species, containing quercetin, luteolin and scutellarein glycosides, showed anti-inflammatory activity by lowering ROS and NO production in LPS-induced inflammation in RAW 264.7 macrophage cells [77]. Extracts from Rhodomyrtus tomentosa, containing the flavonoid quercetin, effectively suppressed the release of NO and prostaglandin E2 in LPS-treated RAW 264.7 cells and peritoneal macrophages [78]. These studies were about anti-inflammatory activity of plant extracts. Extracts are composed of a variety of flavonoids, so the bioactivity cannot be attributed to one specific flavonoid. Nevertheless, there are other studies in which the anti-inflammatory effect of individual flavonoids was evaluated.

In different mice models, apigenin (<10 μM) has shown inhibitory action on NO and prostaglandin E2 (PGE2) by inhibiting the expression of iNOS and COX-2, respectively. Furthermore, apigenin (25 mg/kg) suppressed p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation without affecting the activity of extracellular signal-regulated kinase (ERK) [79]. Apigenin also played a protective role against hepatocarcinogenesis on lipid peroxidation, as an antioxidant defense [80]. Quercetin (10–25 μM) exerted an inhibitory effect on NO and TNF-α on BV-2 LPS-stimulated microglia cells [81]. Furthermore, quercetin (10 μM) down-regulated COX-2 and NF-κB expression and reduced NO production in ochratoxin-stimulated HepG2 (human hepatoma) cells [82]. Luteolin (<10 μM) inhibited NO, IL-6, MCP-1 and TNF-α production, as well as iNOS and COX-2 expression in pseudorabies virus-infected RAW 264.7 cells by inhibiting NF-κB activation [83].

The molecular mechanisms involved in the anti-inflammatory effect of flavonoids might include the inhibition of pro-inflammatory enzymes, such as COX-2 and iNOS; and cytokines, the inhibition of NF-κB, AP-1 and mitogen-activated protein kinase (MAPK) [84,85,86]. Evidence that supports this statement will be discussed next.

Flavonoids as Anti-Cytokine Agents
A large number of phenolic compounds have been reported to inhibit both the secretion and expression of pro-inflammatory cytokines. Regarding the effect of flavonoids on cytokine secretion, it has been observed that apigenin, chrysin, diosmetin, kaempferol, luteolin, naringenin and quercetin, at 50 and 100 nM, reduced IL-6 and TNF-α secretion levels in LPS-stimulated RAW 264.7 macrophages [87]. The incubation of human periodontal ligament cells with apigenin (40 μM) significantly decreased the nicotine- and LPS-induced production of IL-1β, TNF-α, IL-6, and IL-12 [88]. Besides this, it was established that luteolin, quercetin, genistein, kaempferol, apigenin, diosmetin and hesperetin, at 25 and 50 μM, inhibited TNF-α release in LPS-activated macrophages, quercetin, luteolin and genistein being the most efficient inhibitors of this cytokine secretion. Furthermore, quercetin and luteolin exerted stimulatory effects on the expression of the anti-inflammatory cytokine IL-10, but at low concentrations (<50 μM) [89]. Luteolin (15–20 μM) has been proven to exert anti-cytokine effects on IL-1β and TNF-α release by murine BV-2 microgial cells stimulated with LPS/IFN-γ [90]. Moreover, luteolin (3–10 μM) significantly reduced IL-6 and TNF-α release by suppressing NF-κB activity in human monocytes under hyperglycemic conditions (20 mM glucose) [91].Naringenin (10–50 μM), extracted from Nymphaea mexicana Zucc, showed a noticeable inhibitory effect on NO, MCP-1 and TNF-α production in LPS-activated RAW 264.7 macrophages. Naringenin (10–25 μM) also inhibited LPS-mediated induction of protein expressions of iNOS, COX-2, and phospho-ERK [92]. Quercetin and Luteolin, both at 25 μM, effectively inhibited IL-1β, IL-6, IFN-γ and TNF-α production in human whole blood incubated with LPS [93]. A six-week supplementation of quercetin (150 mg) given to human subjects significantly decreased serum concentration of the cytokine TNF-α [94]. In relation to the effect of flavonoids on cytokine expression it has been established that quercetin (100–200 mg/kg), a very known anti-inflammatory flavonoid, reduced pancreatic histopathological damage and reduced the mRNA and protein expression of NF-κB, IL-1β, IL-6 and TNF-α in hypertriglyceridemia-related acute pancreatitis in rats [95]. Apigenin (20 mg/kg) administration to subarachnoid hemorrhage suffering rats significantly attenuated mRNA expression of TNF-α, IL-6 and IL-1β when compared to the untreated control, showing neuroprotective effects [96]. Fisetin (3–30 μM) reduced TNF-α, IL-1β, IL-6 and IL-8 expression and production in phorbol-12-myristate-13-acetate plus calcium ionophore (PMACI)-stimulated human mast cells. Additionally, fisetin inhibited phosphorylation of MAPKs and nuclear translocation of NF-κB induced by PMACI [97]. It has been demonstrated that luteolin-8-C-β-fucopyranoside (LU8C-FP) (50 μM) suppressed the expression levels of IL-6 on phorbol 12-myristate 13-acetate-treated THP-1 cells, a human leukemia monocytic cell line, by inhibiting MAPKs and NF-κB signaling pathways in human monocytic cells. Nevertheless, LU8C-FP failed to inhibit IL-1β and IL-8 expression, which provide information leading to the use of this flavonoid to treat inflammatory diseases caused by IL-6 [98], such as colitis, diabetes, rheumatoid arthritis, cancer and cardiovascular diseases [99,100,101,102,103].

NF-κB and AP-1 are important transcriptional factors in the modulation of pro-inflammatory mediators, like cytokines [85,104]. The first mediates the expression of cytokines and other inflammatory mediators [105], while the second participates in the synthesis of effector molecules and cytokines during innate immune response [106]. Due to the important role of NF-κB and AP-1 in inflammation, studies have been conducted in order to determine the effect of flavonoids in the modulation of these transcriptional factors. Quercetin (100 μM) significantly reduced high glucose-induced increased NF-κB and AP-1 activity by 43% and 69%, respectively, in rat aortic endothelial cells [107]. The treatment of IL-1β-induced human synovial sarcoma cells (SW982) with luteolin (1–10 μM) significantly reduced TNF-α and IL-6 production, inhibited JNK and p38 activation and diminished the activation of NF-κB and AP-1 transcription factors. These findings suggest that the flavonoid luteolin possess anti-cytokine activity in SW982 cells by inhibiting MAPKs (JNK and p38) and transcriptional factors (NF-κB and AP-1) [108].

As mentioned above, cytokine overproduction is highly related to chronic diseases such as Alzheimer's disease, rheumatoid arthritis and cancer, among others [16,109,110]. Flavonoids being able to downregulate cytokine expression and secretion are a very promising alternative to be used as treatment of the diseases mentioned previously. A summary of the studies here addressed is shown in Table 2.

It has been proposed that anti-inflammatory mechanism of flavonoids is highly related to their chemical structure. The main features of flavonoids to exert their anti-inflammatory activity are: (I) a planar ring system in the flavonoid molecule; (II) unsaturation in the C ring at the C2–C3 position; (III) the number and position of hydroxyl groups at the A and B rings, particularly at C5 and C7 in A ring and at C3′ and C4′ in B ring; (IV) the lack of hydroxyl groups on B ring apparently eliminates the activity; (V) the keto group at C4 in C ring, and; (VI) non-glycosylation of the molecule [111,112]. In this regard, flavonoids with hydroxyl groups in 3′ and 4' position, such as quercetin and luteolin, showed higher inhibitory effect on TNF-α release than those with only one hydroxyl group in B ring, namely genistein, regardless of the presence of a double bound in C2–C3 [89]. Luteolin exerts anti-inflammatory activity by inhibiting iNOS, IL-1β, IL-6 and TNF-α expression in LPS-stimulated RAW 264.7 macrophages, while O-glycosylated luteolin showed lower effect on iNOS and IL-1β expression than the aglycone [113]. To a better understanding of structure/anti-inflammatory activity relationship of flavonoids the study by Ribeiro et al. can be reviewed [93].

This evidence highlights that the anti-inflammatory effect of flavonoids by inhibiting expression and secretion of cytokines, as well as diminishing NF-κB and AP-1 activity, as shown in Figure 3.

6. Conclusions
Various inflammatory diseases up-regulate pro-inflammatory cytokines, such as TNF-α and IL-1β, and inflammatory mediators such as NO and prostaglandins, via NF-κB, AP-1 and MAPKs, signal pathways in inflammatory cells. All in all, this manuscript compiled a series of studies that serve as a good basis to support the statement that flavonoids have a promising potential in the development of new drugs to treat inflammation-related diseases. Flavonoids appear to be important modulators of pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α. However, the effect of flavonoids on intracellular signaling pathways and on other inflammatory mediators still remains to be investigated, since it would depend on the type of cells, the studied disease and the applied stimulus. Extensive research in this area is therefore required.

Acknowledgments
This work was financially supported by the Mexican Consejo Nacional de Ciencia y Tecnologia (CONACYT) (Proyecto Ciencia Basica 252416).

Author Contributions
Nayely Leyva-López initiated this review in partial fulfillment of her experiential educations under the supervision of J. Basilio Heredia; both of them contributed with editing of this manuscript; Erick P. Gutierrez-Grijalva and Dulce L. Ambriz-Perez contributed to its writing.

Conflicts of Interest
The authors declare that there are no conflicts of interest.

Abbreviations
AP-1	Activating protein-1	
bDMARD	Biological disease-modifying anti-rheumatic drugs	
COX	Cyclooxygenase	
ERK	Extracellular signal-regulated kinases	
IL	Interleukin	
iNOS	Nitric oxide synthase inducible	
JNK	c-Jun N-terminal kinases	
LPS	Lipopolysaccharide	
MAPKs	Mitogen-activated protein kinases	
MCP-1	Monocyte chemoattractant protein-1	
NF-κB	Nuclear factor kappa-light-chain-enhancer of activated B cells	
NO	Nitric Oxide	
NSAIDs	Nonsteroidal anti-inflammatory drugs	
ROS	Reactive oxygen species	
TLR	Toll-like receptor	
TNF	Tumor necrosis factor	
Figure 1 Basic chemical structure of different flavonoid classes. Structure of (a) basic flavonoid skeleton; (b) flavonols; (c) flavones; (d) flavanones; (e) flavanols; (f) isoflavones and (g) anthocyanidins.

Figure 2 Hypothetical model that shows the possible effect of flavonoids from J. platyphylla on the levels of some inflammatory mediators. Lipopolysaccharide (LPS) binds to TLR4 receptor and triggers the generation of reactive oxygen species (ROS) from nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase and mitochondria. ROS-mediated redox reactions activate the nuclear translocation of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB). The NF-κB activation mediates inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX) expression. Both COX-1 and COX-2 activities mediate the production of prostaglandins. In addition, J. platyphylla total extracts (mixture of flavonoids and lipophilic compounds) inhibited both COX-1 and COX-2 activities. The up black arrow indicates an increase on inflammatory mediators when macrophage cells are stimulated with LPS. The down blue arrow shows suppressive effect on ROS, NO and prostaglandin levels by flavonoids. The red T-shaped symbol indicates inhibition on protein activity. Adapted from Ambriz-Perez, Bang, Nair, Angulo-Escalante, Cisneros-Zevallos and Heredia [76].

Figure 3 Mechanisms involved in the anti-cytokine effect of flavonoids. The red "X" indicates negative regulation of cytokine synthesis by flavonoids.

ijms-17-00921-t001_Table 1Table 1 Drugs used to block cytokine activity 1.

Therapeutic Agent	Mode of Action	Cytokine Targeted	Reference	
Tocilizumab	Anti-IL-6 receptor	IL-6	Oldfield, Dhillon and Plosker [59]	
Ustekinumab	Anti-P40	IL-12/IL-23	Papp, et al. [63]	
Anakinra	IL-1β antagonist	IL-1β	Waugh and Perry [64]	
Amgen	Anti-IL-17	TNF-α	Steinman [65]	
Etanercept	Soluble receptor	TNF-α	[66,67]	
Infliximab	Anti-TNF-α	TNF-α	[67,68]	
Dacliqumab	Anti-IL-2 receptor	IL-2	Martin [69]	
1 Table adapted from Leung, Liu, Fang, Chen, Guo and Zhang [60]. IL: interleukin; TNF: tumor necrosis factor.

ijms-17-00921-t002_Table 2Table 2 Role of flavonoids as cytokine modulators.

Flavonoid	Effect	Molecular Mechanism Involved	Reference	
Apigenin	Reduction of NO and prostaglandin E2 (PGE2) production. Inhibition of IL-6, IL-1β, IL-12 and TNF-α secretion	Inhibition in the iNOS, COX-2, IL-6, IL-1β and TNF-α gene expression. Amelioration of p38-MAPK, JNK and ERK phosphorylation	[79,80,87,88,89,96]	
Fisetin	Decreased TNF-α, IL-1β, IL-6 and IL-8 expression and production	Inhibited p38, JNK and ERK phosphorylation. Inhibited nuclear translocation of NF-κB	[97]	
Luteolin	Reduction of NO, IL-6, MCP-1, TNF-α, IL-1β and IFN-γ production. Stimulation of IL-10 secretion	Reduction of iNOS and COX-2 expression. Inhibition of the JNK and p38 activation. Diminished NF-κB and AP-1 activation	[83,87,89,90,91,93,108]	
Naringenin	Diminished NO, MCP-1, IL-6 and TNF-α secretion	Inhibited iNOS, COX-2 and ERK expression	[87,92]	
Quercetin	Inhibition of NO, TNF-α, IL-1β, IL-6 and interferon (IFN)-γ production. Increased IL-10 secretion	Suppression in the COX-2, TNF-α, IL-1β, IL-6 and NF-κB expression. Inhibition of the NF-κB and AP-1 activity	[81,82,87,89,93,94,95,107]
==== Refs
References
1. Agati G.  Azzarello E.  Pollastri S.  Tattini M.   Flavonoids as antioxidants in plants: Location and functional significance Plant Sci. 2012 196 67 76 10.1016/j.plantsci.2012.07.014 23017900 
2. Babu P.V.A.  Liu D.  Gilbert E.R.   Recent advances in understanding the anti-diabetic actions of dietary flavonoids J. Nutr. Biochem. 2729-15-4177 1729-15-4177/j.jnutbio.2013.06.003 24029069 
3. Jiang W.  Wei H.  He B.   Dietary flavonoids intake and the risk of coronary heart disease: A dose-response meta-analysis of 15 prospective studies Thromb. Res. 2015 135 459 729-15-4177/j.thromres.2014.12.016 25555317 
4. Venturelli S.  Burkard M.  Biendl M.  Lauer U.M.  Frank J.  Busch C.   Prenylated chalcones and flavonoids for the prevention and treatment of cancer Nutrition {{PHONE+SOCIAL_SECURITY_NUMBER}}/j.nut.2016.03.020 27238957 
5. Tunon M.  Garcia-Mediavilla M.  Sanchez-Campos S.  Gonzalez-Gallego J.   Potential of flavonoids as anti-inflammatory agents: Modulation of pro-inflammatory gene expression and signal transduction pathways Curr. Drug Metab. 2009 10 256 729-15-4177/138920009787846369 19442088 
6. Ribeiro D.  Freitas M.  Lima J.L.F.C.  Fernandes E.   Proinflammatory pathways: The modulation by flavonoids Med. Res. Rev. 2015 35 877 936 10.1002/med.21347 25926332 
7. González-Gallego J.  García-Mediavilla M.V.  Sánchez-Campos S.  Tuñón M.J.   Fruit polyphenols, immunity and inflammation Br. J. Nutr. 2010 104 S15 S27 10.1017/S0007114510003910 20955647 
8. Kumar S.  Pandey A.K.   Chemistry and biological activities of flavonoids: An overview Sci. World J. 2013 2013 16 10.1155/2013/162750 24470791 
9. Middleton E.  Kandaswami C.  Theoharides T.C.   The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer Pharmacol. Rev. 2000 52 673 751 11121513 
10. Baecklund E.  Iliadou A.  Askling J.  Ekbom A.  Backlin C.  Granath F.  Catrina A.I.  Rosenquist R.  Feltelius N.  Sundström C.   Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis Arthritis Rheum. 2006 54 692 729-15-4177/art.21675 16508929 
11. Siebert S.  Tsoukas A.  Robertson J.  McInnes I.   Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases Pharmacol. Rev. 2015 67 280 729-15-4177/pr.114.009639 25697599 
12. Medzhitov R.   Origin and physiological roles of inflammation Nature 2008 454 428 729-15-4177/nature07201 18650913 
13. Ashley N.T.  Weil Z.M.  Nelson R.J.   Inflammation: Mechanisms, costs, and natural variation Annu. Rev. Ecol. Evol. Syst. 2012 43 385 729-15-4177/annurev-ecolsys-040212-092530 
14. Kumar V.  Abbas A.K.  Fausto N.  Mitchell R.N.   Robbins Basic Pathology Elsevier Health Sciences Philadephia, PA, USA 2012 
15. Libby P.  Ridker P.M.  Maseri A.   Inflammation and atherosclerosis Circulation 2002 105 1135 1729-15-4177/hc0902.104353 11877368 
16. Azizi G.  Navabi S.S.  Al-Shukaili A.  Seyedzadeh M.H.  Yazdani R.  Mirshafiey A.   The role of inflammatory mediators in the pathogenesis of alzheimer's disease Sultan Qaboos Univ. Med. J. 2015 15 e305 e729-15-41775/squmj.230.255.87.639-848-3083 
17. Rock K.L.  Kono H.   The inflammatory response to cell death Annu. Rev. Pathol. 2008 3 99 10.1146/annurev.pathmechdis.3.121806.151456 18039143 
18. Friedman R.  Hughes A.L.   Molecular evolution of the NF-κB signaling system Immunogenetics 2002 53 964 974 11862396 
19. Proell M.  Riedl S.J.  Fritz J.H.  Rojas A.M.  Schwarzenbacher R.   The nod-like receptor (NLR) family: A tale of similarities and differences PLoS ONE 2008 3 921 10.1371/journal.pone.0002119 18446235 
20. Shaulian E.  Karin M.   AP-1 in cell proliferation and survival Oncogene 2001 20 p2729-15-4177/sj.onc.1204383 11402335 
21. Brzustewicz E.  Bryl E.   The role of cytokines in the pathogenesis of rheumatoid arthritis—Practical and potential application of cytokines as biomarkers and targets of personalized therapy Cytokine 2015 76 527 729-15-4177/j.cyto.2015.08.260 26321413 
22. Singh U.P.  Singh N.P.  Murphy E.A.  Price R.L.  Fayad R.  Nagarkatti M.  Nagarkatti P.S.   Chemokine and cytokine levels in inflammatory bowel disease patients Cytokine 2016 77 44 49 10.1016/j.cyto.2015.10.008 26520877 
23. Jones V.S.  Huang R.-Y.  Chen L.-P.  Chen Z.-S.  Fu L.  Huang R.-P.   Cytokines in cancer drug resistance: Cues to new therapeutic strategies BBA—Rev. Cancer 2016 1865 255 729-15-4177/j.bbcan.2016.03.005 26993403 
24. Han Z.  Boyle D.  Manning A.  Firestein G.   AP-1 and NF-κB regulation in rheumatoid arthritis and murine collagen-induced arthritis Autoimmunity 1998 28 197 729-15-4177/08916939808995367 9892501 
25. Chow C.-W.  Downey G.P.   Chapter 1—Inflammation Clinical Critical Care Medicine Albert R.K.  Slutsky A.S.  Ranieri V.M.  Takala J.  Torres A.   Mosby Philadelphia, PA, USA 2006 1 12 
26. Feghali C.A.  Wright T.M.   Cytokines in acute and chronic inflammation Front. Biosci. 1997 2 d12 d26 9159205 
27. Belkhelfa M.  Rafa H.  Medjeber O.  Arroul-Lammali A.  Behairi N.  Abada-Bendib M.  Makrelouf M.  Belarbi S.  Masmoudi A.N.  Tazir M.    IFN-γ and TNF-α are involved during alzheimer disease progression and correlate with nitric oxide production: A study in algerian patients J. Interferon Cytokine Res. 2014 34 839 729-15-4177/jir.2013.0085 24831467 
28. Chung H.Y.  Cesari M.  Anton S.  Marzetti E.  Giovannini S.  Seo A.Y.  Carter C.  Yu B.P.  Leeuwenburgh C.   Molecular inflammation: Underpinnings of aging and age-related diseases Ageing Res. Rev. 2009 8 18 30 10.1016/j.arr.2008.07.002 18692159 
29. Lee Y.-J.  Han S.B.  Nam S.-Y.  Oh K.-W.  Hong J.T.   Inflammation and alzheimer's disease Arch. Pharm. Res. 2729-15-4177 1729-15-4177/s12272-010-1006-7 21052932 
30. Rogers J.  Lue L.-F.   Microglial chemotaxis, activation, and phagocytosis of amyloid β-peptide as linked phenomena in alzheimer's disease Neurochem. Int. 2001 39 333 729-15-4177/S0197-0186(01)00040-7 11578768 
31. Gabay C.   Interleukin-6 and chronic inflammation Arthritis Res. Ther. 2006 8 S3 10.1186/ar1917 16899107 
32. Zamarron B.F.  Chen W.   Dual roles of immune cells and their factors in cancer development and progression Int. J. Biol. Sci. 2011 7 651 729-15-4177/ijbs.7.651 21647333 
33. Lerkvaleekul B.  Soponkanaporn S.  Vilaiyuk S.   The correlations of serum interleukin-6 (IL-6) levels and serum soluble IL-6 receptor levels with disease activity in systemic juvenile idiopathic arthritis patients with and without tocilizumab treatment Pediatr. Rheumatol. 639-848-3083.1186/1546-0096-12-S1-P61 
34. Yao X.  Huang J.  Zhong H.  Shen N.  Faggioni R.  Fung M.  Yao Y.   Targeting interleukin-6 in inflammatory autoimmune diseases and cancers Pharmacol. Ther. 2014 141 125 729-15-4177/j.pharmthera.2013.09.004 24076269 
35. Vasilopoulos Y.  Sourli F.  Zafiriou E.  Klimi E.  Ioannou M.  Mamuris Z.  Simos G.  Koukoulis G.  Roussaki-Schulze A.   High serum levels of HIF-1α in psoriatic patients correlate with an over-expression of IL-6 Cytokine 2013 62 38 39 10.1016/j.cyto.2013.02.029 23517877 
36. Scheller J.  Ohnesorge N.  Rose-John S.   Interleukin-6 trans -signalling in chronic inflammation and cancer Scand. J. Immunol. 2006 63 321 729-15-4177/j.1365-3083.2006.01750.x 16640655 
37. Blay J.-Y.  Negrier S.  Combaret V.  Attali S.  Goillot E.  Merrouche Y.  Mercatello A.  Ravault A.  Tourani J.-M.  Moskovtchenko J.-F.   Serum level of interleukin 6 as a prognosis factor in metastatic renal cell carcinoma Cancer Res. 1992 52 3317 3322 1596890 
38. Costes V.  Liautard J.  Picot M.C.  Robert M.  Lequeux N.  Brochier J.  Baldet P.  Rossi J.F.   Expression of the interleukin 6 receptor in primary renal cell carcinoma J. Clin. Pathol. 1997 50 835 729-15-4177/jcp.50.10.835 9462266 
39. Tanaka T.  Narazaki M.  Kishimoto T.   Therapeutic targeting of the interleukin-6 receptor Annu. Rev. Pharmacol. Toxicol. 2012 52 199 729-15-4177/annurev-pharmtox-010611-134715 21910626 
40. Atreya R.  Mudter J.  Finotto S.  Müllberg J.  Jostock T.  Wirtz S.  Schütz M.  Bartsch B.  Holtmann M.  Becker C.   Blockade of interleukin 6 trans  signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in crohn disease and experimental colitis in vivo  Nat. Med. 2000 6 583 729-15-4177/nm1110-1341 10802717 
41. Akiyama H.  Arai T.  Kondo H.  Tanno E.  Haga C.  Ikeda K.   Cell mediators of inflammation in the alzheimer disease brain Alzheimer Dis. Assoc. Disord. 2000 14 S47 S53 10.1097/00002093-200000001-00008 10850730 
42. Satpathy A.  Ravindra S.  Thakur S.  Kulkarni S.  Porwal A.  Panda S.   Serum interleukin-1β in subjects with abdominal obesity and periodontitis Obes. Res. Clin. Pract. 2015 9 513 729-15-4177/j.orcp.2015.01.005 25682300 
43. Feldmann M.  Maini R.N.   Anti-TNFα therapy of rheumatoid arthritis: What have we learned? Annu. Rev. Immunol. 2001 19 163 729-15-4177/annurev.immunol.19.1.163 11244034 
44. Kitazawa M.  Yamasaki T.R.  Laferla F.M.   Microglia as a potential bridge between the amyloid β-peptide and Tau Ann. N. Y. Acad. Sci. 2004 1035 85 729-15-4177/annals.1332.006 15681802 
45. Landskron G.  De la Fuente M.  Thuwajit P.  Thuwajit C.  Hermoso M.A.   Chronic inflammation and cytokines in the tumor microenvironment J. Immunol. Res. {{PHONE+SOCIAL_SECURITY_NUMBER}}/639-848-3083 24901008 
46. Sandilands E.A.  Bateman D.N.   Non-steroidal anti-inflammatory drugs Medicine 2016 44 185 729-15-4177/j.mpmed.2015.12.022 
47. MacDonald T.   Epidemiology and pharmacoeconomic implications of non-steroidal anti-inflammatory drug-associated gastrointestinal toxicity Rheumatology 2000 39 13 20 10.1093/rheumatology/39.suppl_2.13 11276797 
48. Herrero J.F.  Romero-Sandoval E.A.  Gaitan G.  Mazario J.   Antinociception and the new cox inhibitors: Research approaches and clinical perspectives CNS Drug Rev. 2003 9 227 729-15-4177/j.1527-3458.2003.tb00251.x 14530796 
49. Warden S.J.   Prophylactic use of nsaids by athletes: A risk/benefit assessment Physician Sports Med. 2010 38 132 729-15-4177/psm.2729-15-4177 20424410 
50. Jones R.  Rubin G.  Berenbaum F.  Scheiman J.   Gastrointestinal and cardiovascular risks of nonsteroidal anti-inflammatory drugs Am. J. Med. 2008 121 464 729-15-4177/j.amjmed.2008.01.045 18501223 
51. Lanas A.  García-Rodríguez L.-A.  Arroyo M.-T.  Gomollón F.  Feu F.  González-Pérez A.  Zapata E.  Bástida G.  Rodrigo L.  Santolaria S.   Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations Gut 2729-15-4177 1729-15-4177/gut.2005.080754 16687434 
52. Arend W.P.   The mode of action of cytokine inhibitors J. Rheumatol. 2002 65 16 21 
53. McGeehan G.M.  Becherer J.D.  Bast R.C.  Boyer C.M.  Champion B.  Connolly K.M.  Conway J.G.  Furdon P.  Karp S.  Kidao S.   Regulation of tumour necrosis factor-α processing by a metalloproteinase inhibitor Nature 1994 370 558 729-15-4177/370558a0 8052311 
54. Thornberry N.A.  Bull H.G.  Calaycay J.R.  Chapman K.T.  Howard A.D.  Kostura M.J.  Miller D.K.  Molineaux S.M.  Weidner J.R.  Aunins J.   A novel heterodimeric cysteine protease is required for interleukin-1βprocessing in monocytes Nature 1992 356 768 729-15-4177/356768a0 1574116 
55. Schreiber G.  Walter M.R.   Cytokine-receptor interactions as drug targets Curr. Opin. Chem. Biol. 2010 14 511 729-15-4177/j.cbpa.2010.06.165 20619718 
56. Emery P.  Keystone E.  Tony H.  Cantagrel A.  van Vollenhoven R.  Sanchez A.  Alecock E.  Lee J.  Kremer J.   IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: Results from a 24-week multicentre randomised placebo-controlled trial Ann. Rheum. Dis. 2729-15-4177 1729-15-4177/ard.2008.092932 18625622 
57. Consortium I.-R.M.R.A.   The interleukin-6 receptor as a target for prevention of coronary heart disease: A mendelian randomisation analysis Lancet 2012 379 1214 1224 22421340 
58. Sebba A.   Tocilizumab: The first interleukin-6-receptor inhibitor Am. J. Health-Syst. Pharm. 2729-15-4177 1729-15-4177/ajhp070449 18653811 
59. Oldfield V.  Dhillon S.  Plosker G.L.   Tocilizumab: A review of its use in the management of rheumatoid arthritis Drugs 2009 69 609 729-15-4177/00003495-200969050-00007 19368420 
60. Leung S.  Liu X.  Fang L.  Chen X.  Guo T.  Zhang J.   The cytokine milieu in the interplay of pathogenic Th1/Th17 cells and regulatory T cells in autoimmune disease Cell. Mol. Immunol. 2010 7 182 729-15-4177/cmi.2729-15-41773174 
61. Genovese M.C.  McKay J.D.  Nasonov E.L.  Mysler E.F.  da Silva N.A.  Alecock E.  Woodworth T.  Gomez-Reino J.J.   Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: The tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study Arthritis Rheum. 2729-15-4177 2980 18821691 
62. So A.  de Smedt T.  Revaz S.  Tschopp J.   A pilot study of IL-1 inhibition by anakinra in acute gout Arthritis Res. Ther. 2007 9 R28 10.1186/ar2143 17352828 
63. Papp K.A.  Langley R.G.  Lebwohl M.  Krueger G.G.  Szapary P.  Yeilding N.  Guzzo C.  Hsu M.-C.  Wang Y.  Li S.   Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (phoenix 2) Lancet 2008 371 1675 1729-15-4177/S0140-6736(08)60726-6 18486740 
64. Waugh J.  Perry C.M.   Anakinra: A review of its use in the management of rheumatoid arthritis Biodrugs 2004 19 189 729-15-4177/00063030-200519030-00005 15984903 
65. Steinman L.   Mixed results with modulation of Th-17 cells in human autoimmune diseases Nat. Immunol. 2010 11 41 44 10.1038/ni.1803 20016509 
66. Dhillon S.  Lyseng-Williamson K.A.  Scott L.J.   Etanercept: A review of its use in the management of rheumatoid arthritis Drugs 2729-15-4177 10.2165/00003495-200767080-00011 17521223 
67. Stübgen J.P.   Tumor necrosis factor-α antagonists and neuropathy Muscle Nerve 2008 37 281 729-15-4177/mus.20924 18041052 
68. Maini R.N.  Breedveld F.C.  Kalden J.R.  Smolen J.S.  Furst D.  Weisman M.H.  St Clair E.W.  Keenan G.F.  van der Heijde D.  Marsters P.A.   Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate Arthritis Rheum. 2729-15-4177 1729-15-4177/art.20159 15077287 
69. Martin R.   Humanized anti-CD25 antibody treatment with daclizumab in multiple sclerosis Neurodegener. Dis. 2008 5 23 26 10.1159/000109934 18075271 
70. Petrussa E.  Braidot E.  Zancani M.  Peresson C.  Bertolini A.  Patui S.  Vianello A.   Plant flavonoids—Biosynthesis, transport and involvement in stress responses Inter. J. Mol. Sci. 2729-15-41770 10.3390/ijms140714950 23867610 
71. Saito K.  Yonekura-Sakakibara K.  Nakabayashi R.  Higashi Y.  Yamazaki M.  Tohge T.  Fernie A.R.   The flavonoid biosynthetic pathway in arabidopsis: Structural and genetic diversity Plant Physiol. Biochem. 2013 72 21 34 10.1016/j.plaphy.2013.02.001 23473981 
72. Lin J.K.  Weng M.S.   Flavonoids as Nutraceuticals The Science Of Flavonoids Grotewold E.   Springer New York, NY, USA 2006 
73. Lopez-Lazaro M.   Distribution and biological activities of the flavonoid luteolin Mini Rev. Med. Chem. 2009 9 31 59 10.2174/138955709787001712 19149659 
74. Maroon J.C.  Bost J.W.  Maroon A.   Natural anti-inflammatory agents for pain relief Surg. Neurol. Int. 2010 1 80 21206541 
75. Nair V.  Bang W.Y.  Schreckinger E.  Andarwulan N.  Cisneros-Zevallos L.   Protective role of ternatin anthocyanins and quercetin glycosides from butterfly pea (clitoria ternatea leguminosae) blue flower petals against lipopolysaccharide (LPS)-induced inflammation in macrophage cells J. Agric. Food Chem. 2729-15-4177 6729-15-4177/acs.jafc.5b00928 26120869 
76. Ambriz-Perez D.L.  Bang W.Y.  Nair V.  Angulo-Escalante M.A.  Cisneros-Zevallos L.  Heredia J.B.   Protective role of flavonoids and lipophilic compounds from jatropha platyphylla on the suppression of lipopolysaccharide (LPS)-induced inflammation in macrophage cells J. Agric. Food Chem. 2729-15-4177 1909 10.1021/acs.jafc.5b05534 26872073 
77. Leyva-López N.  Nair V.  Bang W.Y.  Cisneros-Zevallos L.  Heredia J.B.   Protective role of terpenes and polyphenols from three species of oregano (lippia graveolens, lippia palmeri and hedeoma patens) on the suppression of lipopolysaccharide-induced inflammation in raw 264.7 macrophage cells J. Ethnopharmacol. 2016 187 302 729-15-4177/j.jep.2016.04.051 27131433 
78. Jeong D.  Yang W.S.  Yang Y.  Nam G.  Kim J.H.  Yoon D.H.  Noh H.J.  Lee S.  Kim T.W.  Sung G.-H.    In vitro  and in vivo  anti-inflammatory effect of rhodomyrtus tomentosa methanol extract J. Ethnopharmacol. 2013 146 205 729-15-4177/j.jep.2012.12.034 23295168 
79. Ha S.K.  Lee P.  Park J.A.  Oh H.R.  Lee S.Y.  Park J.H.  Lee E.H.  Ryu J.H.  Lee K.R.  Kim S.Y.   Apigenin inhibits the production of NO and PGE2 in microglia and inhibits neuronal cell death in a middle cerebral artery occlusion-induced focal ischemia mice model Neurochem. Int. 2008 52 878 729-15-4177/j.neuint.2007.10.005 18037535 
80. Prince Vijeya Singh J.  Selvendiran K.  Mumtaz Banu S.  Padmavathi R.  Sakthisekaran D.   Protective role of apigenin on the status of lipid peroxidation and antioxidant defense against hepatocarcinogenesis in wistar albino rats Phytomedicine 2004 11 309 729-15-4177/0944711041495254 15185843 
81. Mrvová N.  Škandík M.  Kuniaková M.  Račková L.   Modulation of BV-2 microglia functions by novel quercetin pivaloyl ester Neurochem. Int. 2015 90 246 729-15-4177/j.neuint.2015.09.005 26386394 
82. Ramyaa P.  Krishnaswamy R.  Padma V.V.   Quercetin modulates OTA-induced oxidative stress and redox signalling in HepG2 cells—Up-regulation of Nrf2 expression and down regulation of Nf-κB and COX-2 BBA—Gen. Subj. 2014 1840 681 729-15-4177/j.bbagen.2013.10.024 24161694 
83. Liu C.-W.  Lin H.-W.  Yang D.-J.  Chen S.-Y.  Tseng J.-K.  Chang T.-J.  Chang Y.-Y.   Luteolin inhibits viral-induced inflammatory response in RAW 264.7 cells via suppression of STAT1/3 dependent NF-κB and activation of HO-1 Free Radic. Biol. Med. 2016 95 180 729-15-4177/j.freeradbiomed.2016.03.019 27016074 
84. Santangelo C.  Varì R.  Scazzocchio B.  Di Benedetto R.  Filesi C.  Masella R.   Polyphenols, intracellular signalling and inflammation Annali-istituto Super. di Sanita 2007 43 394 (In German) 
85. Serafini M.  Peluso I.  Raguzzini A.   Flavonoids as anti-inflammatory agents Proc. Nutr. Soc. 2010 69 273 729-15-4177/S002966511000162X 20569521 
86. García-Lafuente A.  Guillamón E.  Villares A.  Rostagno M.  Martínez J.   Flavonoids as anti-inflammatory agents: Implications in cancer and cardiovascular disease Inflamm. Res. 2009 58 537 729-15-4177/s00011-009-0037-3 19381780 
87. Mueller M.  Hobiger S.  Jungbauer A.   Anti-inflammatory activity of extracts from fruits, herbs and spices Food Chem. 2010 122 987 996 10.1016/j.foodchem.2010.03.041 
88. Jeong G.S.  Lee S.H.  Jeong S.N.  Kim Y.C.  Kim E.C.   Anti-inflammatory effects of apigenin on nicotine- and lipopolysaccharide-stimulated human periodontal ligament cells via heme oxygenase-1 Int. Immunopharmacol. 2009 9 1374 1729-15-4177/j.intimp.2009.08.015 19729077 
89. Comalada M.  Ballester I.  Bailón E.  Sierra S.  Xaus J.  Gálvez J.  de Medina F.S.  Zarzuelo A.   Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: Analysis of the structure–activity relationship Biochem. Pharmacol. 2729-15-4177 1729-15-4177/j.bcp.2006.07.016 16934226 
90. Kao T.-K.  Ou Y.-C.  Lin S.-Y.  Pan H.-C.  Song P.-J.  Raung S.-L.  Lai C.-Y.  Liao S.-L.  Lu H.-C.  Chen C.-J.   Luteolin inhibits cytokine expression in endotoxin/cytokine-stimulated microglia J. Nutr. Biochem. 2011 22 612 729-15-4177/j.jnutbio.2010.01.011 21036586 
91. Kim H.J.  Lee W.  Yun J.-M.   Luteolin inhibits hyperglycemia-induced proinflammatory cytokine production and its epigenetic mechanism in human monocytes Phytother. Res. 2729-15-4177 1729-15-4177/ptr.5141 24623679 
92. Hsu C.-L.  Fang S.-C.  Yen G.-C.   Anti-inflammatory effects of phenolic compounds isolated from the flowers of nymphaea mexicana zucc Food Funct. 2013 4 1216 1729-15-4177/c3fo60041f 23727892 
93. Ribeiro D.  Freitas M.  Tomé S.M.  Silva A.M.S.  Laufer S.  Lima J.L.F.C.  Fernandes E.   Flavonoids inhibit COX-1 and COX-2 enzymes and cytokine/chemokine production in human whole blood Inflammation 2015 38 858 729-15-4177/s10753-014-9995-x 25139581 
94. Egert S.  Bosy-Westphal A.  Seiberl J.  Kürbitz C.  Settler U.  Plachta-Danielzik S.  Wagner A.E.  Frank J.  Schrezenmeir J.  Rimbach G.    Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: A double-blinded, placebo-controlled cross-over study Br. J. Nutr. 2009 102 1065 1729-15-4177/S0007114509359127 19402938 
95. Zheng J.  Wu J.  Chen J.  Liu J.  Lu Y.  Huang C.  Hu G.  Wang X.  Zeng Y.   Therapeutic effects of quercetin on early inflammation in hypertriglyceridemia-related acute pancreatitis and its mechanism Pancreatology 2016 16 200 729-15-4177/j.pan.2016.01.005 26873426 
96. Zhang T.  Su J.  Guo B.  Wang K.  Li X.  Liang G.   Apigenin protects blood-brain barrier and ameliorates early brain injury by inhibiting tlr4-mediated inflammatory pathway in subarachnoid hemorrhage rats Int. Immunopharmacol. 2015 28 79 87 10.1016/j.intimp.2015.05.024 26028151 
97. Park H.-H.  Lee S.  Oh J.-M.  Lee M.-S.  Yoon K.-H.  Park B.H.  Kim J.W.  Song H.  Kim S.-H.   Anti-inflammatory activity of fisetin in human mast cells (HMC-1) Pharmacol. Res. 2007 55 31 37 10.1016/j.phrs.2006.10.002 17079162 
98. Lee Y.S.  Kim M.S.  Lee D.H.  Kwon T.H.  Song H.-H.  Oh S.-R.  Yoon D.Y.   Luteolin 8-C-β-fucopyranoside downregulates IL-6 expression by inhibiting mapks and the NF-κB signaling pathway in human monocytic cells Pharmacol. Rep. 2015 67 581 729-15-4177/j.pharep.2014.12.016 25933972 
99. Ho L.-J.  Luo S.-F.  Lai J.-H.   Biological effects of interleukin-6: Clinical applications in autoimmune diseases and cancers Biochem. Pharmacol. 2015 97 16 26 10.1016/j.bcp.2015.06.009 26080005 
100. Okamoto M.  Kawamata H.  Kawai K.  Oyasu R.   Enhancement of transformation in vitro  of a nontumorigenic rat urothelial cell line by interleukin 6 Cancer Res. 1995 55 4581 4585 7553633 
101. Qu D.  Liu J.  Lau C.W.  Huang Y.   Il-6 in diabetes and cardiovascular complications Br. J. Pharmacol. 2014 171 3595 3729-15-4177/bph.12713 24697653 
102. Li Y.  de Haar C.  Chen M.  Deuring J.  Gerrits M.M.  Smits R.  Xia B.  Kuipers E.J.  van der Woude C.J.   Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis Gut 2010 59 227 729-15-4177/gut.2009.184176 19926618 
103. Semerano L.  Thiolat A.  Minichiello E.  Clavel G.  Bessis N.  Boissier M.-C.   Targeting IL-6 for the treatment of rheumatoid arthritis: Phase II investigational drugs Expert Opin. Investig. Drugs 2014 23 979 999 10.1517/13543784.2014.912276 24766460 
104. Fujioka S.  Niu J.  Schmidt C.  Sclabas G.M.  Peng B.  Uwagawa T.  Li Z.  Evans D.B.  Abbruzzese J.L.  Chiao P.J.   NF-κB and AP-1 connection: Mechanism of NF-κB-dependent regulation of AP-1 activity Mol. Cell. Biol. 2729-15-4177 7729-15-4177/MCB.24.17.7806-7819.2004 15314185 
105. Richmond A.  Yang J.   The role of NF-κB in modulating antitumor immunity OncoImmunology 639-848-3083.1080/2162402X.2015.1005522 26942050 
106. Qiao Y.  He H.  Jonsson P.  Sinha I.  Zhao C.  Dahlman-Wright K.   AP-1 is a key regulator of proinflammatory cytokine tnfα-mediated triple-negative breast cancer progression J. Biol. Chem. {{PHONE+SOCIAL_SECURITY_NUMBER}}/jbc.M115.702571 26792858 
107. Panicker S.R.  Sreenivas P.  Babu M.S.  Karunagaran D.  Kartha C.C.   Quercetin attenuates monocyte chemoattractant protein-1 gene expression in glucose primed aortic endothelial cells through NF-κB and AP-1 Pharmacol. Res. 2010 62 328 729-15-4177/j.phrs.2010.06.003 20542118 
108. Choi E.M.  Lee Y.S.   Luteolin suppresses IL-1β-induced cytokines and MMPs production via p38 MAPK, JNK, NF-κB and AP-1 activation in human synovial sarcoma cell line, SW982 Food Chem. Toxicol. 2729-15-4177 2729-15-4177/j.fct.2010.06.029 20600535 
109. Geng Y.  Chandrasekaran S.  Hsu J.-W.  Gidwani M.  Hughes A.D.  King M.R.   Phenotypic switch in blood: Effects of pro-inflammatory cytokines on breast cancer cell aggregation and adhesion PLoS ONE 639-848-3083.1371/journal.pone.0054959 23372803 
110. Riegsecker S.  Wiczynski D.  Kaplan M.J.  Ahmed S.   Potential benefits of green tea polyphenol EGCG in the prevention and treatment of vascular inflammation in rheumatoid arthritis Life Sci. 2013 93 307 729-15-4177/j.lfs.2013.07.006 23871988 
111. Lago J.  Toledo-Arruda A.  Mernak M.  Barrosa K.  Martins M.  Tibério I.  Prado C.   Structure-activity association of flavonoids in lung diseases Molecules 2729-15-4177 10.3390/molecules19033570 24662074 
112. Gautam R.  Jachak S.M.   Recent developments in anti-inflammatory natural products Med. Res. Rev. 2009 29 767 729-15-4177/med.20156 19378317 
113. Francisco V.  Figueirinha A.  Costa G.  Liberal J.  Lopes M.C.  García-Rodríguez C.  Geraldes C.F.G.C.  Cruz M.T.  Batista M.T.   Chemical characterization and anti-inflammatory activity of luteolin glycosides isolated from lemongrass J. Funct. Foods 2014 10 436 729-15-4177/j.jff.2014.07.003


{'source': 'PubMedDataset'}