FLAVONOIDS: BIOCHEMISTRY, BIOPHYSICS, MEDICINE - Tarakhovsky Yu. S. - 2013

CHAPTER 1. MAJOR FLAVONOIDS

1.9. Anthocyanins (Anthocyanidins)

The word "anthocyanin" is derived from the Greek words anthos meaning "flower" and kyanos meaning "blue." Anthocyanins are brightly colored Flavonoids found within Cell vacuoles. Their vivid hues span almost the entire visible spectrum and are highly dependent on the pH of the medium. Therefore, any description of anthocyanin coloration is largely conditional, as it is shaped by the Specific characteristics of Plant Tissues and environmental conditions.

Anthocyanins determine the coloration of flowers and fruits, and can also be present in other plant parts. For instance, they occur in leaves, where their concentration increases significantly in autumn, producing the red tones of fall foliage, while yellow tones are associated with carotenoids. Notably, anthocyanins are also found in the stems and roots of certain plants. In flowers, anthocyanins play a role in attracting insect pollinators. In leaves, they provide camouflage or a deterrent coloration against pests. Additionally, they can act as a filter protecting the plant from excessive solar radiation. Blackcurrant berries are exceptionally rich in anthocyanins, containing 250 mg of anthocyanins per 100 g of fresh weight, with the majority concentrated in the berry Skin.

Anthocyanin molecules carry a positive charge, which enhances their Water solubility, particularly in acidic environments. Furthermore, in plant tissues, anthocyanins frequently exist in glycosylated forms, which further increases their solubility in water.

1.9.1. Examples of Typical Anthocyanins

To date, more than thirty different monomeric forms of anthocyanins have been identified, with over 90% of all known anthocyanins based on just six distinct molecules: pelargonidin, cyanidin, peonidin, delphinidin, petunidin, and malvidin (Fig. 20). Through combinations with various sugars and polyphenols (mostly flavonoids), these molecules generate a vast array of compounds. Currently, over 500 plant pigments containing anthocyanins have been discovered, and the number of identified substances is growing rapidly alongside advancements in Analytical Methods. The structural diversity of anthocyanins is described in detail in monographs and reviews by various authors.

Class="center">Fig. 20. Anthocyanins and their 3-O-Glycosides.

Aurantinidin is a water-soluble anthocyanin found in evergreen plants of the genus Impatiens—particularly Impatiens platypetala, native to Java and other Indonesian islands—which gives the flowers of this plant their bright orange color. Aurantinidin is also present in the flowers of South American ornamental plants of the Alstroemeria family (order Liliales), where yellow, red, and orange tones predominantly prevail.

Cyanidin is a pigment found in many red berries, including grapes, blueberries, blackberries, bilberries, cherries, cranberries, elderberries, hawthorn, and raspberries, as well as in red onions and red cabbage. Cyanidin exhibits a red color in acidic and mildly acidic environments, whereas its color shifts to violet in neutral or alkaline media. Another notable compound is cyanidin 3-O-glycoside (also known as antirrhin), which is found in the flowers of Antirrhinum majus (snapdragon), blackcurrant (Ribes nigrum), the fruit of the Amazonian acai palm (Euterpe oleracea)—renowned for its medicinal and nutritional properties—and the fruit of the Chinese lychee (Litchi chinensis), commonly known as the Chinese plum. Another 3-O-glycoside of cyanidin, chrysanthemin, is present in blackcurrants, roselle (Hibiscus sabdariffa), the flowers of Rhaponticum scariosum (a member of the Asteraceae family), plums (Prunus domestica), and the fruit of the acai palm (Euterpe oleracea).

Delphinidin imparts a blue coloration to flowers such as the sweet violet (Viola odorata) or larkspur (Delphinium elatum). It also contributes a reddish-blue hue to certain grape varieties and pomegranates (Punica granatum). The delphinidin 3-O-glucosides myrtillin and tulipanin are found in blackcurrants. Myrtillin is also present in blueberries and cranberries, while tulipanin is responsible for the coloration of flowers in tulips (Tulipa), Alstroemeria, barberry (Berberis), Hymenocallis, and cassava (Manihot), and is also present in eggplant fruit (Solanum melongena).

(Berberis), Hymenocallis, cassava (Manihot), and is also present in eggplant fruit (Solanum melongena).

Pelargonidin gives plants an orange hue and is found in the flowers of geraniums (genus Pelargonium, family Geraniaceae), the fruits of raspberries and blackberries (Rubus), strawberries (Fragaria), bilberries and cranberries (Vaccinium), plums (Prunus), and pomegranates (Punica). It is also present in high concentrations in red beans (Phaseolus).

Malvidin, its glucoside oenin, and its galactoside primulin exhibit a blue color and are present in the petals of primroses (Primula) and scarlet pimpernel (Anagallis). Oenin is also found in red grapes and wine.

Petunidin is a water-soluble dark red or purple pigment found in the petals of various petunia species (Petunia). In addition, it occurs in many red or black berries of the Rosaceae family, such as black chokeberry (Aronia melanocarpa), red chokeberry (Aronia arbutifolia), rowanberry (Sorbus aucuparia), Saskatoon berry (Amelanchier alnifolia), and various red grape cultivars (Vitis vinifera, Vitis rotundifolia).

Peonidin is a purple-red pigment discovered in peony petals (Paeonia). It contributes to the coloration of many floral petals, including plants of the morning glory family such as Ipomoea violacea, and is also found in the fruit of various cranberry species (Vaccinium). Peonidin 3-O-glucoside is present in red grape varieties and red onions.

Plants frequently contain more complex molecules that combine cyanidins with other flavonoids, such as catechins, as seen in the catechin-malvidin glycoside molecule (Fig. 20) found in strawberries. An even more complex conjugate of a delphinidin glycoside and kaempferol (Fig. 21A) has been discovered in the pale blue flowers of Agapanthus. In this molecule, a p-coumaroyl delphinidin diglycoside is attached to a kaempferol triglycoside via succinic acid ester linkages. This compound serves as a clear illustration of an anthocyanin pigment composed of different linked molecular building blocks.

Fig. 21. Complex and unusual anthocyanin molecules. A - Delphinidin-kaempferol glycoside. B - Rare anthocyanin derivatives.

Anthocyanins also encompass molecules formed through the modification of anthocyanidins unique to certain plants. For instance, riccionidins (Fig. 21B) have been identified in the liverwort Ricciocarpos natans. Sphagnum moss (Sphagnum) contains sphagnorubin—an anthocyanin that is poorly soluble in water, tightly bound to cell walls, and thus very difficult to extract. Rosacyanin, a purple pigment found in the petals of hybrid roses (Rosa hybrida), is soluble in acidic water-alcohol mixtures but precipitates in neutral media. It is the first discovered anthocyanidin derivative featuring a Substitution at the C4 position.

1.9.2. Intake and Bioavailability of Anthocyanins

Anthocyanins are present in numerous dietary products. In specifically designed hedonic tests conducted with a group of children, it was found that juices and juice blends containing the highest concentrations of anthocyanins—such as a blend of red grape and blueberry juice—were the most preferred. However, questions remain regarding the digestibility of anthocyanins and their potential efficacy in treating internal organ disorders. This is particularly true for large anthocyanin glycoside molecules, which may also incorporate other flavonoids. An investigation into the intestinal epithelial permeability using a Caco-2 cell monolayer model for the flavonoid-anthocyanin dimer (+)-catechin-(4,8)-malvidin-3-O-glucoside demonstrated that this substance crosses the epithelial model better than the catechin-catechin dimer, though less effectively than the catechin monomer or malvidin-3-O-glucoside. Nevertheless, a portion of anthocyanins undergoes degradation within the digestive tract. For instance, cyanidin and pelargonidin break down into protocatechuic acid and 4-hydroxybenzoic acid. Already in The Stomach, approximately 20% of anthocyanins may degrade, whereas their glycosides remain intact. During subsequent pancreatic enzyme Treatment and intestinal Digestion processes, pelargonin-3-glucoside retains its stability, whereas the content of cyanidin-3-glucoside decreases by 30%. Following absorption into the bloodstream and delivery to the Liver, these compounds undergo further metabolic transformations. In The Endoplasmic reticulum of hepatocytes, 65% of pelargonin glycosides are converted into 4-hydroxybenzoic acid and glucuronic conjugates, while 43% of cyanidin glycosides yield protocatechuic acid and three distinct glucuronic conjugates. The aglycones of these anthocyanins degrade completely. The remaining fraction of anthocyanin glycosides may circulate in the Blood in free form. The systemic absorption of anthocyanins from juices has also been demonstrated in in vivo experiments with mice and in clinical trials. Following the ingestion of 0.8 mg of anthocyanins per kg of body weight by human volunteers, peak blood concentrations of these substances (32.7 ± 2.9 nmol/L) were observed 1.3 hours post-consumption. The maximum rate of urinary excretion of anthocyanins was also recorded During the first two hours. However, the total urinary excretion of anthocyanins over the first 24 hours did not exceed 0.25%.

1.9.3. Antioxidant Activity

The Antioxidant Properties of various fruit juices generally correlate with their content of anthocyanins and other polyphenols, although to varying degrees across different components. For instance, monomeric anthocyanins in cherry juice range from 350-633 mg/L, with cyanidin-3-glucosylrutinoside being the principal component (140-320 mg/L). A significant correlation was found between the juice's antioxidant capacity and the concentration of this specific substance, whereas the correlation with total monomeric anthocyanins was negligible. Conversely, an analysis of differently pigmented rice varieties reveals a weak correlation between antioxidant activity and rice anthocyanins, namely cyanidin-3-glucoside, peonidin-3-glucoside, and malvidin. This suggests that the primary antioxidant activity of rice extract is driven by other polyphenolic compounds rather than anthocyanins. An evaluation of the radical-scavenging capacity of anthocyanins in retinal Cells demonstrated that anthocyanin oligomers exhibit exceptionally high activity, comparable to that of vitamin E. Furthermore, anthocyanins upregulated The activity of superoxide dismutase, catalase, Glutathione peroxidase, and glutathione-S-transferase. These compounds inhibited Cell Cycle arrest in retinal pigment epithelium cells (ARPE-19) induced by hydrogen peroxide. Daily intake of grape skin extract improved plasma antioxidant status in rats under both normal conditions and carbon tetrachloride-induced oxidative stress.

Extraction of anthocyanins using methanol yields significantly higher concentrations of these compounds compared to aqueous extracts. Methanolic extract from blackcurrant fruit was found to mitigate ultraviolet-induced oxidative damage in keratinocytes. Additionally, anthocyanins upregulated the expression of cellular antioxidant Enzymes: catalase, mitochondrial superoxide dismutase MnSOD (or SOD2), glutathione peroxidase (Gpx1/2), and glutathione-S-transferase (Gsta1). A similar protective effect was observed with hibiscus anthocyanin extract (Hibiscus sabdariffa), which effectively scavenged radicals and enhanced cellular antioxidant defense enzymes.

1.9.4. Anticarcinogenic Effect

In vitro experiments revealed that blackcurrant pomace skin consumption has the potential to prevent The Development of hepatocellular carcinoma by suppressing tumor cell proliferation. The protective efficacy of these compounds was also confirmed in animal models where liver carcinogenesis was induced by diethylnitrosamine.

A more cost-effective source of anthocyanins for preventing carcinogenesis is anthocyanin-rich black grape pomace extract, the effects of which have been studied in animals regarding intestinal adenoma. When investigating The impact of red grape and bilberry extracts on human colorectal carcinoma cells, these agents were found to protect DNA from Damage caused by topoisomerase dysfunction under METABOLISM/18.html">The Influence of topoisomerase inhibitors, such as doxorubicin. The authors caution that high Dietary intake of anthocyanins may interfere with the therapeutic efficacy of doxorubicin.

Black rice anthocyanins, when consumed at a dose of 100 mg/kg body weight, can significantly inhibit mammary tumor growth, as demonstrated in animal models as well as human breast Cancer cells. This protective action was accompanied by down-Regulation of the tumor angiogenesis factors MMP-9, MMP-2, and uPA. A comparable effect was observed with red sorghum anthocyanins. These compounds induced apoptosis in human breast cancer cells, which was accompanied by characteristic DNA fragmentation.

The anticarcinogenic activity of individual anthocyanins was also evaluated. Specifically, delphinidin can inhibit glyoxalase-1, an enzyme responsible for removing methylglyoxal—a Glycolysis byproduct capable of triggering apoptosis. A comparative analysis of delphinidin, cyanidin, and pelargonidin showed that delphinidin possesses the highest potency. Only delphinidin suppressed glyoxalase activity to an extent where intracellular accumulation of methylglyoxal triggered apoptosis in human leukemia HL-60 cells. Delphinidin and cyanidin, but not pelargonidin and malvidin, exhibited selective cytotoxic activity against LoVo and LoVo/ADR Colorectal Cancer cells while sparing normal Caco-2 cells. Their mechanism involves the accumulation of reactive oxygen species, inhibition of glutathione reductase, and glutathione depletion. Delphinidin promotes autophagosome and autolysosome formation, thereby inducing autophagy in HeLa Cervical cancer cells. Studies on breast cancer cells indicate that delphinidin inhibits HER2 Tyrosine protein kinase and extracellular signal-regulated kinase Erk1/2 signaling pathways, resulting in growth suppression. Evidently, anthocyanins can trigger different apoptotic pathways across various cancer types. For instance, delphinidin and cyanidin-3-rutinoside induce necrosis in hepatocellular carcinoma cells, which appears to be linked to the induction of autophagy and is completely abolished by 3-methyladenine, an inhibitor of phosphoinositide 3-kinase that regulates autophagic processes.

Cyanidin can help prevent skin cancer by suppressing ultraviolet-Induced Expression of cyclooxygenase COX-2. This effect is achieved through the downregulation of mitogen-activated protein Kinases MKK4 and MEK1, as well as the proto-oncogenic protein kinase Raf-1, via direct binding. Cyanidin-3-glucoside can directly interact with and inhibit oncogenic tyrosine kinase, thereby suppressing COX-2 expression and blocking the Fyn regulatory signaling pathway. Furthermore, cyanidin-3-glucoside inhibits ethanol-induced metastatic factors in breast cancer cells, reducing cell migration, cell-Cell Adhesion, and invasion through lamellipodia formation. This effect is mediated by inhibiting the ethanol-induced phosphorylation of signaling Proteins such as the epidermal growth factor receptor ErbB2 and focal adhesion kinase FAK, which are involved in promoting cell migration and invasion. Lung Cancer metastasis can also be suppressed by peonidin-3-glucoside, which inhibits cancer Cell Motility and invasion by downregulating the phosphorylation of extracellular signal-regulated kinase ERK1/2, a member of the MAPK family. Thus, it is hypothesized that peonidin-3-glucoside exerts its effects via the MAPK regulatory pathway.

As noted above, anthocyanins exhibit low systemic bioavailability due to degradation. However, their degradation products have also been shown to possess anticarcinogenic properties. Specifically, gallic acid and 3-O-methylgallic acid, generated in the gut through Microbial Degradation of anthocyanins, were shown to reduce colorectal cancer cell viability significantly more effectively than malvidin-3-glucoside by inhibiting the Transcription factors NF-$\kappa$B, AP-1, STAT-1, and OCT-1.

1.9.5. Neuroprotective Effect

Anthocyanins can exert a positive influence on cognitive function. Animal studies have demonstrated that anthocyanin-rich mulberry fruit (Morus atropurpurea) can delay Aging processes and the progression of Alzheimer's disease. The brains of mice fed an anthocyanin-supplemented diet exhibited lower amyloid-beta levels, enhanced antioxidant enzyme activity, and reduced Lipid Peroxidation products, alongside improvements in Learning and Memory capabilities. In rats with experimentally induced diabetes, long-term administration of cyanidin-3-glucoside substantially restored memory and learning functions. Cyanidin-O-3-glucopyranoside exerted a neuroprotective effect against toxic amyloid-beta Polypeptides, reducing neuronal cell death via apoptosis and necrosis while preventing the binding of amyloid polypeptides to the neuronal Plasma Membrane and subsequent membrane integrity disruption.

An investigation into the therapeutic efficacy of blueberry anthocyanins in Spinal Cord injury revealed that animals receiving these anthocyanins (20 mg/kg body weight) recovered locomotor function significantly faster, exhibited reduced neuronal loss, and formed a smaller post-traumatic glial scar. Cyanidin-3-O-glucoside from cherries and total raspberry anthocyanin extracts also exhibited protective effects during focal cerebral ischemia. These effects were accompanied by reduced superoxide levels and the blockade of mitochondrial apoptosis-inducing factor release, leading to diminished neuronal death. A similar protective action was observed with mulberry-derived cyanidin-3-glucoside under experimentally induced oxygen-glucose deprivation in animal brains. Moreover, cyanidin-3-glucoside protects the developing fetal Brain against the neurotoxic effects of alcohol. Glycogen synthase kinase 3$\beta$ (GSK3$eta$) is known to act as a mediator of neuronal cell death, with its elevated activity serving as a primary driver of alcohol-induced neurodegeneration. Intraperitoneal administration of this anthocyanin was found to inhibit GSK3$eta$ activity, which was also accompanied by a reduction in alcohol-triggered caspase-3 activation, lower levels of malondialdehyde, and decreased cytosolic neutrophil factor p47phox in Neurons, thereby preventing neuronal apoptosis.

1.9.6. Protection of The Cardiovascular system

The Effects of Flavonoids on the cardiovascular system are highly versatile. A comparative study on the effects of flavanones, flavanols, flavones, anthocyanins, and flavan-3-ols on blood pressure and vascular elasticity, conducted among 1,898 British women aged 18 to 75, statistically and reliably demonstrated the ability of anthocyanins to lower blood pressure and improve vascular elasticity in the Arterial System. Meanwhile, the intake of other flavonoids, as well as wine consumption, showed no effect. Although The Effect of anthocyanins was statistically significant, it should be noted that the observed changes were modest. The changes in systolic blood pressure were -3.0 ± 1.4 mm Hg, mean arterial pressure - -2.3 ± 1.2 mm Hg, and pulse rate - -0.4 ± 0.2 beats/sec. A decrease in upper intravenous pressure was also observed in experiments on rats treated with cyanidin-O-glucopyranoside. The blood pressure-lowering ability is likely related to the fact that anthocyanins, such as delphinidin and cyanin, block the renin-angiotensin blood pressure hormonal regulation signaling system through the inhibition of angiotensin-converting enzyme activity. Furthermore, anthocyanins act at the genetic level, being capable of suppressing renin mRNA production and, consequently, lowering the level of this hormone in the blood.

It is well known that platelet aggregation is a key factor in the development of atherosclerosis. It has been discovered that delphinidin-3-glucoside can inhibit platelet activation and thereby significantly suppress thrombus formation in Blood Vessels. This effect is associated with a decrease in the phosphorylation of platelet adenosine monophosphate-activated protein kinase. In addition, a study on the effects of black rice anthocyanins revealed the suppression of platelet hyperactivity through a reduction in the levels of thromboxane A(2), prostacyclin, water-soluble P-selectin, and Blood Plasma calmodulin.

Furthermore, bilberry anthocyanins are capable of lowering blood Cholesterol levels by normalizing hepatic clearance processes. This is also accompanied by a reduction in blood lipid oxidation products, the suppression of inflammatory processes, and an enhancement of epithelial barrier function due to increased cell-cell adhesion and decreased intercellular space permeability. A decrease in blood cholesterol levels was also observed upon the action of cyanidin-3-O-β-glucoside, which concurrently increased endothelial NO synthase activity and elevated blood NO levels.

Anthocyanins, such as delphinidin, can protect the vascular endothelium and prevent the development of inflammatory processes in The Vascular System by reducing the levels of lipid oxidation products, enhancing the cellular antioxidant defense system, and increasing blood nitric oxide levels. Malvidin-3-glucoside also protects endothelial cells by preventing apoptosis through the inhibition of the mitochondrial apoptotic signaling pathway. This is accompanied by the activation of caspase-3 and -9, and an upregulation of the Bax protein. Furthermore, an increase in blood NO Biosynthesis is observed, along with the upregulation of cyclooxygenase COX-2 and interleukins IL-6 due to the suppression of nuclear factor NF-κB activity.

1.9.7. Anti-inflammatory Activity

The anti-inflammatory effect of anthocyanins was demonstrated in an experiment involving 150 volunteers suffering from hypercholesterolemia, whose diets were supplemented with 320 mg of an anthocyanin mixture daily for 24 weeks. The results showed a significant reduction in plasma inflammation markers, such as high-sensitivity C-reactive protein (hsCRP) and soluble vascular cell adhesion molecule-1 (sVCAM-1), alongside a decreased concentration of low-density Lipoproteins and an increased concentration of high-density lipoproteins, which is a favorable indicator in the treatment of atherosclerosis.

The anti-inflammatory effects of various anthocyanins are also extensively studied using tissue cell cultures. For instance, cyanidin-3-O-β-D-glucoside from black rice and its common blood-borne biodegradation products—cyanidin and protocatechuic acid—exhibit anti-inflammatory effects on RAW 264.7 macrophages. This is accompanied by the suppression of pro-inflammatory cytokine production, tumor necrosis factor TNF-α, and interleukin IL-1β. The levels of inflammatory mediators such as NO and prostaglandin E2 are reduced, alongside a downregulation of the genes for nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Thus, this regulatory effect is mediated through signaling pathways leading to the nuclear transcription factor NF-κB and mitogen-activated protein kinase (MAPK), which are involved in the Gene Expression of inflammatory processes. A similar effect of this anthocyanin was discovered in human THP-1 monocytes; however, According to the authors of this study, the suppression of NF-κB activity in this case was associated with the inhibition of nuclear factor IκBα phosphorylation, which prevents the binding of the NF-κB transcription factor to the DNA molecule. Investigating the effect of cyanidin-3-O-β-D-glucoside on mast cells revealed its ability to suppress anaphylactic reactions associated with histamine release, which was also mediated through the NF-κB and p38MAPK signaling pathways.

In a Study of the effects of pomegranate-derived delphinidin on MH7A fibroblast-like synoviocytes, a suppression of NF-κB gene expression and pro-inflammatory cytokine genes was observed, which has the potential to impede the development of rheumatoid Arthritis. Furthermore, it was shown for the first time that the action of delphinidin is mediated through the inhibition of histone acetyltransferase (HAT) and, consequently, the suppression of the Acetylation of the p65 subunit (also known as RELA), which is part of the NF-κB nuclear transcription factor. Thus, delphinidin was classified as an inhibitor of histone acetyltransferase, an enzyme involved in the Introduction/30.html">Regulation of Gene Expression.

1.9.8. Protection Against Diabetes and Obesity

The ability of anthocyanins to prevent fat accumulation and the development of prediabetic states, as well as to alleviate type 2 diabetes, has been established by numerous researchers, as reflected in a recently published review. For example, a study on the effect of strawberry anthocyanins on postprandial changes in substance concentrations in overweight patients showed that strawberry anthocyanins, particularly pelargonidin-3-O-glucoside, are capable of initiating a significant reduction in inflammatory factors and an increase in tissue sensitivity to Insulin. In another study involving a group of patients with hypercholesterolemia, it was demonstrated that a purified anthocyanin fraction (300 mg daily) improves endothelial function, prevents inflammatory processes, and normalizes plasma lipid profiles. The MOLECULAR MECHANISMS OF anthocyanin action have been studied across various tissue cells. These studies are typically conducted using cyanidin-3-O-glucoside from black beans as a widely distributed and accessible representative of anthocyanins. Research has shown that cyanidin-3-O-glucoside is capable of enhancing cellular insulin sensitivity in various tissues, lowering blood sugar, free fatty acid, and triglyceride levels, and decreasing blood concentrations of inflammatory markers such as tumor necrosis factor TNF-α, interleukin IL-6, and monocyte chemoattractant protein-1. Concurrently, fat accumulation decreased in visceral adipose tissue, the liver, blood plasma, and Muscle tissue, while lipoprotein lipase activity was activated, whereas its activity decreased in adipose tissue. Cyanidin-3-glucoside, much like cyanidin-3-galactoside, exhibited an inhibitory effect on intestinal sucrases and maltases, as well as on pancreatic amylase, thereby reducing sugar digestibility. Furthermore, a synergistic effect was discovered between cyanidin, its glycosides, and the antidiabetic drug acarbose, which also inhibits the digestion and assimilation of sugars in the Small Intestine.

There are many diverse opinions regarding the potential mechanisms behind such versatile actions of anthocyanins in diabetes Prevention. In a study investigating the ability of bilberry anthocyanins to improve cellular insulin sensitivity in mice, it was found that this effect may be achieved through the activation of AMP-activated protein kinase (AMPK). Indeed, AMPK is known to be a regulator of fatty acid β-oxidation processes and the glucose transporter GLUT4. Cyanidin-3-glucoside is capable of reducing insulin resistance by modulating the activity of c-Jun N-terminal kinase, which is involved in the Regulation of Cell proliferation and apoptosis, or through its action on the peroxisome proliferator-activated receptor gamma (PPAR-γ), which participates in The regulation of sugar and fatty acid metabolism [556], or via the transcription factor FOXO1, which is involved in the insulin-dependent regulation of Gluconeogenesis and Glycogenolysis.