ESRRG (estrogen-related receptor gamma)
Structural activity relationship of flavonoids with estrogen‐related receptor to ERR gamma (uniprotkb:P) by surface plasmon resonance. Effects of flavonoids on the activities of ERβ and estrogen‐related receptor γ ( ERRγ). (A) HeLa cells were transfected with an expression. ESRRG (estrogen-related receptor gamma), Authors: Rebecca B Riggins. been shown to be inhibited by kaempferol, a dietary flavonoid (Wang et al., ) . .. Identification and structure-activity relationship of phenolic acyl hydrazones as.
Oligomeric flavonoids may be hydrolyzed to monomers and dimers under influence of acidic conditions in the stomach. Larger molecules reach the colon where they are degraded by bacteria. The sugar moiety of flavonoid glycosides is an important determinant of their bioavailability. Dimerization has been shown to reduce bioavailability. Among all the subclasses of flavonoids, isoflavones exhibit the highest bioavailability [ 65 ].
After ingestion of green tea, flavonoid content is absorbed rapidly as shown by their elevated levels in plasma and urine.
They enter the systemic circulation soon after ingestion and cause a significant increase in plasma antioxidant status [ 66 ]. Compartments involved in the metabolism of flavonoid. Biological Activities of Flavonoids 5. Antioxidant Activity Flavonoids possess many biochemical properties, but the best described property of almost every group of flavonoids is their capacity to act as antioxidants.
The antioxidant activity of flavonoids depends upon the arrangement of functional groups about the nuclear structure. The configuration, substitution, and total number of hydroxyl groups substantially influence several mechanisms of antioxidant activity such as radical scavenging and metal ion chelation ability [ 467 ].
The B ring hydroxyl configuration is the most significant determinant of scavenging of ROS and RNS because it donates hydrogen and an electron to hydroxyl, peroxyl, and peroxynitrite radicals, stabilizing them and giving rise to a relatively stable flavonoids radical [ 68 ].
Mechanisms of antioxidant action can include 1 suppression of ROS formation either by inhibition of enzymes or by chelating trace elements involved in free radical generation; 2 scavenging ROS; and 3 upregulation or protection of antioxidant defenses [ 6970 ].
Structural activity relationship of flavonoids with estrogen-related receptor gamma.
Flavonoid action involves most of the mechanisms mentioned above. Some of the effects mediated by them may be the combined result of radical scavenging activity and the interaction with enzyme functions. Flavonoids inhibit the enzymes involved in ROS generation, that is, microsomal monooxygenase, glutathione S-transferase, mitochondrial succinoxidase, NADH oxidase, and so forth [ 71 ]. Lipid peroxidation is a common consequence of oxidative stress.
Flavonoid protect lipids against oxidative damage by various mechanisms [ 551 ]. Free metal ions enhance ROS formation by the reduction of hydrogen peroxide with generation of the highly reactive hydroxyl radical.
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Due to their lower redox potentials flavonoids Fl-OH are thermodynamically able to reduce highly oxidizing free radicals redox potentials in the range 2.
Because of their capacity to chelate metal ions iron, copper, etc. Quercetin in particular is known for its iron-chelating and iron-stabilizing properties. Trace metals bind at specific positions of different rings of flavonoid structures [ 73 ]. The binding sites are shown in Figure 4 b. This trait of flavonoids makes them most effective scavengers of peroxyl, superoxide, and peroxynitrite radicals [ 4 ].
Epicatechin and rutin are strong radical scavengers and inhibitors of lipid peroxidation in vitro [ 74 ]. Because of oxidation on the B ring of flavonoids having catechol group a fairly stable orthosemiquinone radical is formed which is strong scavengers.
Flavones lacking catechol system on oxidation lead to formation of unstable radicals exhibit weak scavenging potential [ 75 ]. The literature shows that flavonoids having an unsaturated bond in conjugation with a 4-oxo function are more potent antioxidants than the flavonoids lacking one or both features.
Conjugation between the A and B rings allows a resonance effect of the aromatic nucleus that provides stability to the flavonoid radical. Free radical scavenging by flavonoids is potentiated by the presence of both the elements besides other structural features [ 76 ].
The flavonoid heterocycle contributes to antioxidant activity by permitting conjugation between the aromatic rings and the presence of a free 3-OH. Removal of a 3-OH annuls coplanarity and conjugation which compromises scavenging ability [ 77 ]. Generally O-methylation of hydroxyl groups of flavonoids decreases their radical scavenging capacity [ 76 ]. Occurrence, position, structure, and total number of sugar moieties in flavonoid flavonoids glycosides play an important role in antioxidant activity.
Aglycones are more potent antioxidants than their corresponding glycosides. There are reports that the antioxidant properties of flavonol glycosides from tea declined as the number of glycosidic moieties increased [ 78 ]. Though glycosides are usually weaker antioxidants than aglycones, bioavailability is sometimes enhanced by a glucose moiety.
In the diet, flavonoid glycosidic moieties occur most frequently at the 3- or 7-position [ 79 ]. Increasing degree of polymerization enhances the effectiveness of procyanidins against a variety of radical species. Procyanidin dimers and trimers are more effective than monomeric flavonoids against superoxide anion. Tetramers exhibit greater activity against peroxynitrite and superoxide mediated oxidation than trimers, while heptamers and hexamers demonstrate significantly greater superoxide scavenging properties than trimers and tetramers [ 80 ].
Structural activity relationship of flavonoids with estrogen-related receptor gamma.
Hepatoprotective Activity Several flavonoids such as catechin, apigenin, quercetin, naringenin, rutin, and venoruton are reported for their hapatoprotective activities [ 81 ]. Different chronic diseases such as diabetes may lead to development of hepatic clinical manifestations. Anthocyanins have drawn increasing attention because of their preventive effect against various diseases.
Increased Gclc expression results in a decrease in hepatic ROS levels and proapoptotic signaling. Furthermore, C3G treatment lowers hepatic lipid peroxidation, inhibits the release of proinflammatory cytokines, and protects against the development of hepatic steatosis [ 82 ]. Silymarin is a flavonoids having three structural components silibinin, silydianine, and silychristine extracted from the seeds and fruit of milk thistle Silybum marianum Compositae. Silymarin has been reported to stimulate enzymatic activity of DNA-dependent RNA polymerase 1 and subsequent biosynthesis of RNA and protein, resulting in DNA biosynthesis and cell proliferation leading to liver regeneration only in damaged livers [ 83 ].
Silymarin increases proliferating hepatocytes in response to FB1 Fumonisin B1, a mycotoxin produced by Fusarium verticillioides induced cell death without modulation of cell proliferation in normal livers. Silymarin has clinical applications in the treatment of cirrhosis, ischemic injury, and toxic hepatitis induced by various toxins such as acetaminophen, and toxic mushroom [ 85 ].
Hepatoprotective activities were observed in flavonoids isolated from Laggera alata against carbon-tetrachloride CCl4- induced injury in primary cultured neonatal rat hepatocytes and in rats with hepatic damage.
Histopathological examinations also revealed the improvement in damaged liver with the treatment of flavonoid [ 86 ]. Several clinical investigations have shown the efficacy and safety of flavonoids in the treatment of hepatobiliary dysfunction and digestive complaints, such as sensation of fullness, loss of appetite, nausea, and abdominal pain. Equisetum arvense flavonoids as well as hirustrin and avicularin isolated from some other sources is reported to provide protection against chemically induced hepatotoxicity in HepG2 cells [ 8788 ].
Antibacterial Activity Flavonoids are known to be synthesized by plants in response to microbial infection; thus it should not be surprising that they have been found in vitro to be effective antimicrobial substances against a wide array of microorganisms. Flavonoid rich plant extracts from different species have been reported to possess antibacterial activity [ 70728990 ].
Several flavonoids including apigenin, galangin, flavone and flavonol glycosides, isoflavones, flavanones, and chalcones have been shown to possess potent antibacterial activity [ 91 ].
Antibacterial flavonoids might be having multiple cellular targets, rather than one specific site of action. One of their molecular actions is to form complex with proteins through nonspecific forces such as hydrogen bonding and hydrophobic effects, as well as by covalent bond formation. Thus, their mode of antimicrobial action may be related to their ability to inactivate microbial adhesins, enzymes, cell envelope transport proteins, and so forth.
Lipophilic flavonoids may also disrupt microbial membranes [ 9293 ]. Catechins, the most reduced form of the C3 unit in flavonoid compounds, have been extensively researched due to their antimicrobial activity. These compounds are reported for their in vitro antibacterial activity against Vibrio cholerae, Streptococcus mutans, Shigella, and other bacteria [ 9495 ].
The catechins have been shown to inactivate cholera toxin in Vibrio cholera and inhibit isolated bacterial glucosyltransferases in S. Naringenin and sophoraflavanone G have intensive antibacterial activity against methicilline resistant Staphylococcus aureus MRSA and streptococci. An alteration of membrane fluidity in hydrophilic and hydrophobic regions may be attributed to this effect which suggests that these flavonoids might reduce the fluidity of outer and inner layers of membranes [ 99 ].
The correlation between antibacterial activity and membrane interference supports the theory that flavonoids may demonstrate antibacterial activity by reducing membrane fluidity of bacterial cells.
A hydroxyl group at position 5 in flavanones and flavones is important for their activity against MRSA. Substitution with C8 and C10 chains may also enhance the antistaphylococcal activity of flavonoids belonging to the flavanol class [ ].
Haraguchi and colleagues [ ] studied antibacterial activity of two flavonoids, licochalcones A and C, isolated from the roots of Glycyrrhiza inflata against S. This activity was similar to the mode of action of antibiotics inhibiting respiratory chain, since energy is required for active uptake of various metabolites as well as for biosynthesis of macromolecules.
After further studies it was suggested that the inhibition site of these flavonoids was between CoQ and cytochrome in the bacterial respiratory electron transport chain [ ]. There are many examples that lend support to the prowess of phytoconstituents derived from edible and medicinal plants as potent antibacterial agents [ — ].
Anti-Inflammatory Activity Inflammation is a normal biological process in response to tissue injury, microbial pathogen infection, and chemical irritation. Inflammation is initiated by migration of immune cells from blood vessels and release of mediators at the site of damage.
This process is followed by recruitment of inflammatory cells, release of ROS, RNS, and proinflammatory cytokines to eliminate foreign pathogens, and repairing injured tissues. In general, normal inflammation is rapid and self-limiting, but aberrant resolution and prolonged inflammation cause various chronic disorders [ ]. The immune system can be modified by diet, pharmacologic agents, environmental pollutants, and naturally occurring food chemicals.
Certain members of flavonoids significantly affect the function of the immune system and inflammatory cells [ ]. A number of flavonoids such as hesperidin, apigenin, luteolin, and quercetin are reported to possess anti-inflammatory and analgesic effects. Flavonoids may affect specifically the function of enzyme systems critically involved in the generation of inflammatory processes, especially tyrosine and serine-threonine protein kinases .
The inhibition of kinases is due to the competitive binding of flavonoids with ATP at catalytic sites on the enzymes. These enzymes are involved in signal transduction and cell activation processes involving cells of the immune system. It has been reported that flavonoids are able to inhibit expression of isoforms of inducible nitric oxide synthase, cyclooxygenase, and lipooxygenase, which are responsible for the production of a great amount of nitric oxide, prostanoids, leukotrienes, and other mediators of the inflammatory process such as cytokines, chemokines, or adhesion molecules [ ].
Flavonoids also inhibit phosphodiesterases involved in cell activation. Much of the anti-inflammatory effect of flavonoid is on the biosynthesis of protein cytokines that mediate adhesion of circulating leukocytes to sites of injury.
Certain flavonoids are potent inhibitors of the production of prostaglandins, a group of powerful proinflammatory signaling molecules [ ]. Reversal of the carrageenan induced inflammatory changes has been observed with silymarin treatment. It has been found that quercetin inhibit mitogen stimulated immunoglobulin secretion of IgG, IgM, and IgA isotypes in vitro [ ].
Several flavonoids are reported to inhibit platelet adhesion, aggregation, and secretion significantly at 1—10 mM concentration [ ]. The effect of flavonoid on platelets has been related to the inhibition of arachidonic acid metabolism by carbon monoxide [ ]. Alternatively, certain flavonoids are potent inhibitors of cyclic AMP phosphodiesterase, and this may in part explain their ability to inhibit platelet function. Anticancer Activity Dietary factors play an important role in the prevention of cancers.
Fruits and vegetables having flavonoids have been reported as cancer chemopreventive agents [ 72]. In addition, moderate wine drinkers also seem to have a lower risk to develop cancer of the lung, endometrium, esophagus, stomach, and colon [ ].
The critical relationship of fruit and vegetable intake and cancer prevention has been thoroughly documented. It has been suggested that major public health benefits could be achieved by substantially increasing consumption of these foods [ ]. Several mechanisms have been proposed for the effect of flavonoids on the initiation and promotion stages of the carcinogenicity including influences on development and hormonal activities [ ].
Major molecular mechanisms of action of flavonoids are given as follows: Mutations of p53 are among the most common genetic abnormalities in human cancers. The inhibition of expression of p53 may lead to arrest the cancer cells in the G2-M phase of the cell cycle.
Flavonoids are found to downregulate expression of mutant p53 protein to nearly undetectable levels in human breast cancer cell lines [ ]. Tyrosine kinases are a family of proteins located in or near the cell membrane involved in the transduction of growth factor signals to the nucleus.
Their expression is thought to be involved in oncogenesis via an ability to override normal regulatory growth control. Drugs inhibiting tyrosine kinase activity are thought to be possible antitumor agents without the cytotoxic side effects seen with conventional chemotherapy.
Quercetin was the first tyrosine kinase inhibiting compound tested in a human phase I trial [ ]. Heat shock proteins form a complex with mutant p53, which allows tumor cells to bypass normal mechanisms of cell cycle arrest.
Heat shock proteins also allow for improved cancer cell survival under different bodily stresses. Flavonoids are known to inhibit production of heat shock proteins in several malignant cell lines, including breast cancer, leukemia, and colon cancer [ ].
Recently it has been shown that the flavanol epigallocatechingallate inhibited fatty acid synthase FAS activity and lipogenesis in prostate cancer cells, an effect that is strongly associated with growth arrest and cell death . In contrast to most normal tissues expression of FAS is markedly increased in various human cancers. Upregulation of FAS occurs early in tumor development and is further enhanced in more advanced tumors [ ]. Quercetin is known to produce cell cycle arrest in proliferating lymphoid cells.
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In addition to its antineoplastic activity, quercetin exerted growth-inhibitory effects on several malignant tumor cell lines in vitro. It has been experimentally proved that increased signal transduction in human breast cancer cells is markedly reduced by quercetin acting as an antiproliferative agent [ ]. Barnes [ ] has extensively reviewed the anticancer effects of genistein on in vitro and in vivo models.
In an study to determine effects of isoflavones genistein, daidzein, and biochanin A on mammary carcinogenesis, genistein was found to suppress the development of chemically induced mammary cancer without reproductive or endocrinological toxicities. Neonatal administration of genistein a flavonoid exhibited a protective effect against the subsequent development of induced mammary cancer in rats [ ].
Hesperidin, a flavanone glycoside, is known to inhibit azoxymethanol induced colon and mammary cancers in rats [ ]. The anticancer properties of flavonoids contained in citrus fruits have been reviewed by Carroll et al. Several flavonols, flavones, flavanones, and the isoflavone biochanin A are reported to have potent antimutagenic activity [ ].
A carbonyl function at C-4 of the flavone nucleus was found to be essential for their activity. Flavoneacetic acid has also been shown to have antitumor effects [ ]. In earlier studies ellagic acid, robinetin, quercetin, and myricetin have been shown to inhibit the tumorigenicity of BP-7, 8-diol-9, and epoxide-2 on mouse skin [ ]. Higher consumption of phytoestrogens, including isoflavones and other flavonoids, has been shown to provide protection against prostate cancer risk [ ].
It is well known that due to oxidative stress cancer initiation may take place and thus potent antioxidants show potential to combat progression of carcinogenesis.
Potential of antioxidant as an anticancer agent depends on its competence as an oxygen radical inactivator and inhibitor [ 7072]. Therefore diets rich in radical scavengers would diminish the cancer-promoting action of some radicals [ ].
Antiviral Activity Natural compounds are an important source for the discovery and the development of novel antiviral drugs because of their availability and expected low side effects.
Naturally occurring flavonoids with antiviral activity have been recognized since the s and many reports on the antiviral activity of various flavonoids are available. Search of effective drug against human immunodeficiency virus HIV is the need of hour. Most of the work related with antiviral compounds revolves around inhibition of various enzymes associated with the life cycle of viruses.
Structure function relationship between flavonoids and their enzyme inhibitory activity has been observed. Gerdin and Srensso [ ] demonstrated that flavano1 was more effective than flavones and flavonones in selective inhibition of HIV-1, HIV-2, and similar immunodeficiency virus infections.
Baicalin, a flavonoid isolated from Scutellaria baicalensis Lamieaceaeinhibits HIV-1 infection and replication. Baicalein and other flavonoids such as robustaflavone and hinokiflavone have also been shown to inhibit HIV-1 reverse transcriptase [ ]. Another study revealed inhibition of HIV-1 entry into cells expressing CD4 and chemokine coreceptors and antagonism of HIV-1 reverse transcriptase by the flavone O-glycoside [ ].
Flavonoid such as demethylated gardenin A and robinetin are known to inhibit HIV-1 proteinase [ ]. It has also been reported that the flavonoids chrysin, acacetin, and apigenin prevent HIV-1 activation via a novel mechanism that probably involves inhibition of viral transcription [ ].
Various combinations of flavones and flavonols have been shown to exhibit synergism. Kaempferol and luteolin show synergistic effect against herpes simplex virus HSV. Synergism has also been reported between flavonoids and other antiviral agents. Quercetin is reported to potentiate the effects of 5-ethyldioxyuridine and acyclovir against HSV and pseudorabies infection [ ].
Studies have displayed that flavonols are more active than flavones against herpes simplex virus type 1 and the activity order was found to be galangin, kaempferol, and quercetin [ ]. Many flavonoids, namely, dihydroquercetin, dihydrofisetin, leucocyanidin, pelargonidin chloride, and catechin, show activity against several types of virus including HSV, respiratory syncytial virus, polio virus and Sindbis virus [ ].
Inhibition of viral polymerase and binding of viral nucleic acid or viral capsid proteins have been proposed as antiviral mechanisms of action [ ]. List of some flavonoids and their efficacy against viruses is given in Table 4. Antiviral activity of various flavonoids. Role of Flavonoids in Plants 6. Combating Oxidative Stress Flavonoids have long been reported as serving multiple functions in plants [ ]. Various abiotic and biotic factors helps in the generation of ROS in plants leading to oxidative stress.
Flavonoid biosynthesis in plants is almost exclusively enhanced due to oxidative stress. They have capacity to absorb the most energetic solar wavelengths i. Schematic of ERRgamma domain structure. Like most nuclear receptors, the activation function -1 AF1 domain of ERRgamma participates in the regulation of transcription by the receptor.
It is the region to which several coactivators can bind see belowas well as the site of post-translational modification. Phosphorylation of the family member ERRalpha at serine 19 has recently been shown to direct subsequent SUMOylation at a nearby lysine residue 14and that this series of post-translational modifications is in fact inhibitory for receptor transcriptional activity Vu et al.
A key difference between ERRgamma and most members of the nuclear receptor superfamily is the regulation of its transcriptional activity. Therefore, while ERalpha like most nuclear receptors is dependent upon ligand for full activation, ERRgamma and the other members of the ERR family exhibit constitutive transcriptional activity.
ERRgamma constitutive activity has also recently been shown to be inhibited by kaempferol, a dietary flavonoid Wang et al. Like other nuclear receptors, ERRgamma transcriptional activity is modulated by binding to other proteins that can serve as coactivators or corepressors.
Coactivators and corepressors bind directly to nuclear receptors, most often within the carboxyl-terminal activation function-2 AF2 domain that participates in ligand-binding but some can exert their effects by binding to the amino-terminal AF1 domain or the flexible hinge region of the receptor Hall and McDonnell, TLE1 can also enhance ERRgamma activity by binding to its AF1 domain, and the coactivator function of TLE1 in this context is unique because this protein typically functions as a repressor for Drosophila and mammalian high mobility group HMG box transcription factors.
TLE1 also has no known interactions with classical ERalpha or any other nuclear receptor Hentschke and Borgmeyer, Expression In fetal and adult human tissues, ERRgamma1 and ERRgamma2 are most highly expressed in the heart, brain, kidney, and skeletal muscle Heard et al.
Interestingly, in the mouse ERRgamma is also expressed in these tissues but is even more abundant in the brain stem and spinal cord http: As a member of the nuclear receptor superfamily, ERRgamma is a transcription factor.