**2.2 How can polyphenols limit inflammation?**

There are several potential ways in which polyphenols can help to moderate the inflammation levels: these include targets in the signaling pathways, limitation of reactive oxygen species and reactive nitrogen species. Once generated the reaction oxygen or nitrogen species can result in reactive organic molecules as well. These reactive compounds can cause damage to the cells' genetic material, lipids found throughout the body especially in cell membranes and proteins required for cell structure and repair [11, 12].

Polyphenols show considerable potential to regulate oxidative stress and therefore inhibit inflammation [13–15]. Reactive oxygen species (ROS) are generated readily by metabolic reactions and include hydrogen peroxide, superoxide and hydroxyl radicals. These ROS can be particularly troublesome when they interact with nitric oxide in the blood vessels because nitrogen reactive species peroxynitrite is produced. Similarly, ROS and lipids circulating in the arteries can react to form oxidized lipid which can worsen the development of atherosclerosis. Some polyphenols, such as flavonoids, have the ability to scavenge superoxide and peroxynitrite thus inactivating them and preventing the almost certain cell damage [16].

In addition to inactivating ROS and peroxynitrite, some polyphenols also chelate the metal ions required for creation of these reactive species thus inhibiting their activation [17].

Several studies have identified signaling protein and transcription factor targets that can be affected by polyphenols [18–20]. In many cases the polyphenols target multiple proteins within a cascade of responses that can alter not only inflammatory response, but also mediate expression of cell death genes and metabolic function. Although initially the effect on inflammation will be discussed, there is significant overlap in signaling cascades that result in multiple effects.

Available data trends demonstrate that polyphenols are able, in part, to help regulate the expression of nuclease factor kappa beta (NF-κβ), a transcription factor that is expressed during conditions of oxidative stress [18]. NF-κβ binds to DNA when active and functions as a positive transcription factor for a variety of pro-inflammatory cytokines. An increase in inflammation can result in increased levels of TNF-α, interleukin-6 (IL-6) and enzymes inducible nitric oxide synthase and cyclooxygenase 2. Inducible nitric oxidase synthase is responsible for the production of the reactive nitrogen peroxynitirite, and cyclooxygenase 2 catalyzes the production of prostaglandins. The ability of polyphenols to interact with these factors identifies polyphenols as potentially healthful food bioactive that can help fight both the results of inflammation as well as the disease that cause inflammation. Curcumin, a polyphenol found in turmeric root, has been shown to block activation of NF-κβ, thus blocking this pathway and excluding NF-κβ from the nucleus [18]. Similarly, some polyphenols can decrease NF-κβ activity by directly interacting with subunits of the factor [21].

Some polyphenols have been found to activate the transcription factor Nrf2, which when expressed at high levels protects the cells from the damaging effects of reactive oxygen species and inflammatory markers [20, 22]. Nrf2 is a key inducer of protective mechanisms against oxidative stress, leading towards increased production of enzymes such as superoxide dismutase, catalase, and glutathione-s transferases, all of which help to modulate the ROS produced. Polyphenols have been shown to increase nuclear translocation of Nrf2, thus allowing increase transcription of the oxidative stress protective genes [22].

## **3. Metabolic effects**

#### **3.1 Metabolic dysregulation**

The loss of proper metabolic regulation results in a variety of disease states including those associated with chronic inflammation mentioned above. Some such diseases include obesity, diabetes, hyperlipidemia, and type 2 diabetes. Patients that develop a dysregulated metabolism also tend to experience chronic inflammation and vice versa. The two health concerns feed off of each other. Metabolic dysregulation historically has been assigned to lifestyle and diet only, but more recently consideration of multigenerational epigenetic effects and environmental contributions have been included as a cause for the beginning of metabolic dysregulation [23–25]. The days of it being dismissed as caused completely by the patient are or should be past. Fetal programming has been adopted as a significant cause of metabolic syndrome in offspring that can lead to the development of obesity and insulin resistance [26–29].

Many epigenetic modifications lead to changes in metabolic function. One such example is acetyl-CoA carboxylase, the enzyme the converts acetyl-CoA into malonyl-CoA for entry into the fatty acid synthesis pathway. Galdieri and Vancura

#### *Therapeutic Potential of Dietary Polyphenols DOI: http://dx.doi.org/10.5772/intechopen.99177*

have demonstrated that this enzyme aids in regulation of histone acetylation. Specifically they have identified that histone acetylation, one major method of epigenetic control, depends on acetyl-Co generated prior to entry into the Kreb's cycle that can be limited in conditions where acetyl-CoA carboxylase is expressed at higher levels. Interestingly, they noted that the acetyl-CoA required to acetylate histones for transcriptional regulation was more readily available when expression of acetyl-Co carboxylase was limited [30].

The importance of this acetyl-CoA – histone acetylation connection is that a global connection between metabolic activity and the transcriptional control of all genes. Any upregulation in the acetyl-CoA carboxylase, which you would expect in individuals with excessive glucose intake due to either limited balanced meal options or overindulgence in high carbohydrate foods, could potentially be inhibiting their ability to acetylate histones. Additional enzymes that contribute to the intercellular concentration of acetyl-CoA, such as ATP citrate lyase have also been identified [31]. ATP citrate lyase converts citrate formed in the first step of the Kreb's cycle to acetyl-CoA. Again this further demonstrates how food intake and availability can be communicated to cells in such a way that allows gene transcription to be silenced or enhanced.

Histone acetylation is catalyzed by histone acetyl transferases (HATs) and responsible for reprogramming gene expression along with histone deacetylases (HDACs). In general acetylation of histones in a specific gene region will increase expression of the gene, while deacetylation (catalyzed by HDACs) decreases gene expression of subsequent genes. Polyphenols have been shown to interact considerably with the HAT and HDAC enzymes and therefore have the potential to assist with re-regulation of metabolism.

#### **3.2 Polyphenol potential for re-regulation**

Numerous studies have demonstrated the potential to reverse, at least partially, some of the changes resulting from metabolic dysregulation [32–35]. Reversing or alleviating some of the inflammation associated with conditions such as metabolic syndrome may help to mediate the increased risk of cardiovascular disease with these conditions. The incidences of cardiovascular disease and diabetes are increasing globally and polyphenols offer a natural, inexpensive way to help slow the development of the comorbidities associated with these disease states. In most cases the effectiveness of the polyphenol treatment comes from its effects on insulin resistance and inflammatory reduction [32, 33, 36]. Although there seems to be significant effects on improving health with the use of dietary polyphenols, the more comorbidities a patient suffers from, the more unlikely it will benefit them to the extent necessary. For this reason, it is important that patients hoping to achieve results from polyphenol consumption begin polyphenol therapy at the first sign of metabolic dysregulation or perhaps even better, begin using polyphenols as a preventative measure. Few studies have been conducted that look at polyphenol use as an adjunctive therapy for metabolic conditions, but rather as a potential sole therapy. Similarly, the effectiveness of polyphenol therapy alone show strong ties to specific populations [34].

As discussed previously, availability of acetyl-CoA is controlled by metabolic enzymes and dietary input. Levels of acetyl-CoA also affect histone acetylation which can control transcription of a variety of genes. A proposed link of HAT activity to diabetes exists because of the interaction between the HAT, glucokinase and hepatocyte nuclear factor that relates to a transcriptional change rather than a true epigenetic change [35]. The transcriptional changes come from the increase in acetylation marks present because of the HAT activity that interacts with the

gene promoter for pro-inflammation gene products that depend also on NF-κβ for expression [35]. This example demonstrates yet another link between diseases of metabolic dysregulation and those of inflammation or cancer.

In terms of therapeutic potential of polyphenol for metabolic dysregulation, it seems that enhancing acetylation of histones is not the only benefit of consumption. Polyphenols, particularly those found in cinnamon, improve insulin resistance and improve lipid profile [32, 33, 37, 38]. Some clinical studies have demonstrated reductions of 12.9–52.2 mg/dL in blood glucose levels while others have found less robust and potentially null effects [38–40].
