Myricitin
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Myricetin is a member of the
flavonoid Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...
class of polyphenolic compounds, with antioxidant properties. Common dietary sources include vegetables (including
tomato The tomato (, ), ''Solanum lycopersicum'', is a plant whose fruit is an edible Berry (botany), berry that is eaten as a vegetable. The tomato is a member of the nightshade family that includes tobacco, potato, and chili peppers. It originate ...
es), fruits (including
oranges The orange, also called sweet orange to distinguish it from the bitter orange (''Citrus × aurantium''), is the fruit of a tree in the family Rutaceae. Botanically, this is the hybrid ''Citrus'' × ''sinensis'', between the pomelo (''Citrus m ...
), nuts, berries, tea, and red wine. Myricetin is structurally similar to
fisetin Fisetin (7,3′,4′- flavon-3-ol) is a plant flavonol from the flavonoid group of polyphenols. It occurs in many plants where it serves as a yellow pigment A pigment is a powder used to add or alter color or change visual appearance. Pig ...
,
luteolin Luteolin is a flavone, a type of flavonoid, with a yellow crystalline appearance. Luteolin is the main yellow dye from the '' Reseda luteola'' plant, used for dyeing since at least the first millennium B.C. Luteolin was first isolated in pure f ...
, and
quercetin Quercetin is a plant flavonol from the flavonoid group of polyphenols. It is found in many fruits, vegetables, leaves, seeds, and grains; capers, red onions, and kale are common foods containing appreciable amounts of it. It has a bitter flavor ...
and is reported to have many of the same functions as these other members of the
flavonol Flavonols are a class of flavonoids that have the 3-hydroxyflavone backbone (IUPAC name: 3-hydroxy-2-phenylchromen-4-one). Their diversity stems from the different positions of the phenolic –OH groups. They are distinct from flavanols (with ...
class of flavonoids. Reported average intake of myricetin per day varies depending on diet, but has been shown in the Netherlands to average 23 mg/day. Myricetin is produced from the parent compound
taxifolin Taxifolin (5,7,3',4'-flavan-on-ol), also known as dihydroquercetin, belongs to the subclass flavanonols in the flavonoids, which in turn is a class of polyphenols. It is extracted from plants such as Siberian larch and milk thistle. Stereocent ...
through the (+)-dihydromyricetin intermediate and can be further processed to form
laricitrin Laricitrin is an ''O''-methylated flavonol, a type of flavonoid. It is found in red grape (absent in white grape) and in '' Vaccinium uliginosum'' (bog bilberries). It is one of the phenolic compounds present in wine. Metabolism Laricitrin is ...
and then
syringetin Syringetin is an ''O''-methylated flavonol, a type of flavonoid. It is found in red grape (absent in white grape), in '' Lysimachia congestiflora'' and in '' Vaccinium uliginosum'' (bog bilberries). It is one of the phenolic compounds present in ...
, both members of the flavonol class of flavonoids. Dihydromyricetin is frequently sold as a supplement and has controversial function as a partial GABAA receptor potentiator and treatment in Alcohol Use Disorder (AUD). Myricetin can alternatively be produced directly from
kaempferol Kaempferol (3,4′,5,7-tetrahydroxyflavone) is a natural flavonol, a type of flavonoid, found in a variety of plants and plant-derived foods including kale, beans, tea, spinach, and broccoli. It is also found in propolis extracts. Kaempferol i ...
, which is another flavonol.


Sources


Oxidative Properties


Antioxidant

Antioxidants Antioxidants are Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...
are molecules present in fruits and vegetables that have been demonstrated to protect against some forms of cancer and cardiovascular disease. Biomolecules and cell structures can experience oxidative stress due to the presence and activity of
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
(ROS). ROS like •OH, •O2, and H2O2 are produced during cellular metabolism processes (
aerobic respiration Cellular respiration is the process of oxidizing biological fuels using an inorganic electron acceptor, such as oxygen, to drive production of adenosine triphosphate (ATP), which stores chemical energy in a biologically accessible form. Cellu ...
). ROS can damage lipids, DNA, and proteins. Gradual but steady accretion of such damage can lead to the development of many diseases and conditions including thrombosis, diabetes, persistent inflammation, cancer, and atherosclerosis. Flavonoids including myricetin are able to scavenge for ROS and can
chelate Chelation () is a type of bonding of ions and their molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These l ...
intracellular transition metal ions that ultimately produce ROS. Myricetin also enhances the effects of other antioxidants. Myricetin can induce the enzyme
glutathione S-transferase Glutathione ''S''-transferases (GSTs), previously known as ligandins, are a family of eukaryote, eukaryotic and prokaryote, prokaryotic Biotransformation#Phase II reaction, phase II metabolic isozymes best known for their ability to Catalysis, ...
(GST). GST has been suggested to protect cells against oxidative stress by protecting cells against free-radicals. ''In vitro'' studies have shown that myricetin significantly increased GST activity.


Pro-oxidant

Multiple studies have demonstrated that myricetin also has the potential to act as a
pro-oxidant Pro-oxidants are chemicals that induce oxidative stress, either by generating reactive oxygen species or by inhibiting antioxidant systems. The oxidative stress produced by these chemicals can damage cells and tissues, for example, an overdose of ...
due to its tendency to undergo
autoxidation Autoxidation (sometimes auto-oxidation) refers to oxidations brought about by reactions with oxygen at normal temperatures, without the intervention of flame or electric spark. The term is usually used to describe the gradual degradation of organi ...
depending upon its environment . It has been seen that when in the presence of cyanide, autoxidation is favored, resulting in superoxide, a byproduct characteristic of causing cellular damage . However, sodium azide,
superoxide dismutase Superoxide dismutase (SOD, ) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide () anion radical into normal molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxy ...
, and
catalase Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting ...
have been seen to inhibit the autoxidation of myricetin. Myricetin may also act as a pro-oxidant in its ability to increase the production of
hydroxy radical The hydroxyl radical, •HO, is the neutral form of the hydroxide ion (HO–). Hydroxyl radicals are highly reactive and consequently short-lived; however, they form an important part of radical chemistry. Most notably hydroxyl radicals are pr ...
s through reactions with Fe2+ or Fe3+
EDTA Ethylenediaminetetraacetic acid (EDTA), also called EDTA acid, is an aminopolycarboxylic acid with the formula . This white, slightly water-soluble solid is widely used to bind to iron (Fe2+/Fe3+) and calcium ions (Ca2+), forming water-solubl ...
and
hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...
. The resulting hydroxy radicals are often linked to DNA degradation, however, there are doubts as to whether or not this damage would be significant when analyzed ''in vivo'' since ''in vitro'' studies with both
bovine Bovines (subfamily Bovinae) comprise a diverse group of 10 genera of medium to large-sized ungulates, including Bos, cattle, bison, African buffalo, Bubalus, water buffalos, and the four-horned and spiral-horned antelopes. The members of this gro ...
and human
serum albumin Serum albumin, often referred to simply as blood albumin, is an albumin (a type of globular protein) found in vertebrate blood. Human serum albumin is encoded by the ''ALB'' gene. Other mammalian forms, such as bovine serum albumin, are chem ...
exhibited extensive protection against it. Myricetin's pro-oxidative capabilities can also be seen in its ability to act as an inhibitory agent against
glutathione reductase Glutathione reductase (GR) also known as glutathione-disulfide reductase (GSR) is an enzyme that in humans is encoded by the GSR gene. Glutathione reductase (EC 1.8.1.7) catalyzes the reduction of glutathione disulfide ( GSSG) to the sulfhydryl ...
, which is responsible for regenerating
glutathione Glutathione (GSH, ) is an organic compound with the chemical formula . It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources ...
, a scavenger of
free radicals In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired electron, unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemical reaction, chemi ...
and peroxides.


Potential health effects


Anticarcinogen

Myricetin is also effective in protecting cells from
carcinogen A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and biologic agents such as viruse ...
ic mutation. Myricetin reduces the risk of skin tumorigenicity that is caused by
polycyclic aromatic hydrocarbons A Polycyclic aromatic hydrocarbon (PAH) is any member of a class of organic compounds that is composed of multiple fused aromatic rings. Most are produced by the incomplete combustion of organic matter— by engine exhaust fumes, tobacco, incin ...
like
benzo(a)pyrene Benzo 'a''yrene (B''a''P or B ) is a polycyclic aromatic hydrocarbon and the result of incomplete combustion of organic matter at temperatures between and . The ubiquitous compound can be found in coal tar, tobacco smoke and many foods, espe ...
, a highly carcinogenic compound. Myricetin provided protection against the formation of skin tumors in mice models after tumor initiating and tumor promoter agents were applied to the skin. On a more biochemical level, it was shown that
topical A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...
application of myricetin to mice inhibited the binding of benzo(a)pyrenes to DNA and protein native to epidermal skin cells. Myricetin also has been shown to inhibit the act of genetic mutation as exhibited by the
Ames test The Ames test is a widely employed method that uses bacteria to test whether a given chemical can cause mutations in the DNA of the test organism. More formally, it is a bioassay, biological assay to assess the mutagenic potential of chemical com ...
. This test showed that myricetin was more effective in preventing mutagenesis initiated by certain carcinogenic polycyclic aromatic hydrocarbons (benzo(a)pyrene, dibenzo(a,h)pyrene, and dibenzo(a,i)pyrene) as compared to others in which it was less effective in preventing against mutagenesis (benzo(a)pyrene 4, 5-oxide and the bay-region diol-epoxides of benzo(a)anthracene, chrysene, and benzo(c)phenathrene). This data shows that myricetin is not unilaterally able to reduce the carcinogenic activity of all polycyclic aromatic hydrocarbons or even the more specific subclass of benzo(a)pyrenes. Myricetin’s exact biochemical activity is still not fully understood. Clearly there is a multifaceted, complex system involved in the anticarcinogenic activity displayed by myricetin that does not apply equally to all carcinogens of the same subfamily.


Mutagen

It has also been shown that myricetin can itself act as an agent of mutagenicity. Myricetin can produce
frameshift mutations A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels ( insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet nature ...
in the genomes of particular strains of ''Salmonella typhimurium''. In general, biochemical structural studies have shown that flavonoid structures can
tautomer In chemistry, tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the reloca ...
ize in biological systems to become active mutagens.


Interactions with DNA

Myricetin can act as a
pro-oxidant Pro-oxidants are chemicals that induce oxidative stress, either by generating reactive oxygen species or by inhibiting antioxidant systems. The oxidative stress produced by these chemicals can damage cells and tissues, for example, an overdose of ...
compound when it interacts with DNA. Studies involving ''in vitro'' models have shown that myricetin causes the degradation of DNA. Additionally, myricetin, in the presence of Fe3+ and Cu2+, intensified this DNA degradation. The antioxidants catalase, superoxide dismutase, mannitol, and sodium azide in combination with Cu2+ increased the DNA degradation activity of myricetin. Myricetin was shown to create
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
that caused the DNA damage. It has been demonstrated that myricetin, depending on its concentration, displays different oxidizing effects on DNA. Polyphenols like myricetin are able to reduce (donate electrons to) Fe3+. Thus, this reaction yields a less oxidized (more reduced) form of the iron cation: Fe2+ and a less reduced (more oxidized) form of myricetin. This allows myricetin to form a complex with oxygen and biochemically target the DNA molecule. At higher and higher concentrations of myricetin, the rate of DNA damage has been shown to decrease. A current hypothesis for why this occurs can be attributed to myricetin’s ability to
chelate Chelation () is a type of bonding of ions and their molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These l ...
iron (Fe) (myricetin ligand forms two or more coordinate bonds to iron). These ''in vitro'' studies cannot be correlated directly to human models and should not be extrapolated. Myricetin also impacts the biochemical efficacy and binding ability of large intracellular biomolecules. Myricetin has been shown to inhibit viral
reverse transcriptase A reverse transcriptase (RT) is an enzyme used to convert RNA genome to DNA, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, by retrotransposon mobi ...
, cellular
DNA polymerase A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create t ...
, and cellular
RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that catalyzes the chemical reactions that synthesize RNA from a DNA template. Using the e ...
. Inhibition of cellular DNA polymerases could have dangerous effects on the cell’s ability to replicate its genome and its progression through the
cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
. Inhibition of cellular RNA polymerase could have deleterious effects on the cell’s capacity to transcribe and translate DNA and RNA to produce vital proteins for the cell. Researchers have found that myricetin has the ability to interfere in the RNA polymerase pathway in two different ways. In ''E. coli'' myricetin competitively inhibited GTP substrate binding to RNA polymerase. In T7
bacteriophages A bacteriophage (), also known informally as a phage (), is a virus that infects and replicates within bacteria. The term is derived . Bacteriophages are composed of proteins that encapsulate a DNA or RNA genome, and may have structures tha ...
myricetin competitively inhibited DNA template binding to RNA polymerase.


Antiviral

Myricetin has been seen to demonstrate antiviral activity against a number of viruses including
Moloney murine leukemia virus Moloney may refer to: * Moloney (surname), people with the surname ''Moloney'' * ''Moloney'' (TV series), 1996–97 American television police drama See also * Maloney *Moloney's Mimic Bat Moloney's mimic bat (''Mimetillus moloneyi'') is a speci ...
, Rauscher murine leukemia virus, and the
human immunodeficiency virus The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause AIDS, acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of th ...
. Its effects against the proliferation of viruses is thought to be a consequence of myricetin’s ability to inhibit the proper functioning of
reverse transcriptase A reverse transcriptase (RT) is an enzyme used to convert RNA genome to DNA, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, by retrotransposon mobi ...
. Myricetin was identified as a
competitive inhibitor Competitive inhibition is interruption of a chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for binding or bonding. Any metabolic or chemical messenger system can potentially be affected b ...
of the reverse transcriptase of Rauscher murine leukemia virus and a partial competitor with respect to the human immunodeficiency virus. Investigations into the activity of the HIV-1 strain when introduced to myricetin suggest the antiviral effects are derived from the inhibition of HIV-1
integrase Retroviral integrase (IN) is an enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme ...
, however, there are suspicions that the inhibition is non-specific. Structural analysis of myricetin and other flavonoids with observed antiviral effects indicate that the 3,4’ free hydroxyl groups likely are responsible for inhibition.


Antithrombotic

Polyphenol Polyphenols () are a large family of naturally occurring phenols. They are abundant in plants and structurally diverse. Polyphenols include phenolic acids, flavonoids, tannic acid, and ellagitannin, some of which have been used historically as ...
s such as myricetin may prevent oxidative stress-induced
platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
activation/aggregation. Thus, consumption of antioxidants may serve an anti-thrombotic function. In addition to offering protection by neutralizing peroxide radicals and effecting
thromboxane Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring. Thromboxane is named for ...
production via the
PTGS1 Cyclooxygenase 1 (COX-1), also known as prostaglandin-endoperoxide synthase 1 ( HUGO PTGS1), is an enzyme that in humans is encoded by the ''PTGS1'' gene. In humans it is one of three cyclooxygenases. History Cyclooxygenase (COX) is the centr ...
pathway, polyphenols such as myricetin may target other platelet activation pathways, limiting fibrinogen’s ability to bind platelet surface receptors.


Antidiabetic

Several ''in vitro'' and animal studies have indicated the antidiabetic capabilities of myricetin; however, the evidence in clinical trials is less convincing. The flavonoid has been demonstrated to have a hypoglycemic effect by increasing the ability of adipocytes, as well as cells of the soleus muscle and liver of rats, to uptake glucose. This insulinomimetic effect is hypothesized to be a consequence of myricetin's either direct or indirect interaction with
GLUT4 Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the ''SLC2A4'' gene. GLUT4 is the insulin-regulated glucose transporter found primarily in ad ...
, however, no analysis has produced concrete conclusions detailing exactly from where this effect is derived. In the hepatocytes of rats suffering from diabetes, myricetin has been observed to increase the activity of glycogen synthase 1. In trials done on ''
Xenopus laevis The African clawed frog (''Xenopus laevis''), also known as simply xenopus, African clawed toad, African claw-toed frog or the ''platanna'') is a species of African aquatic frog of the family Pipidae. Its name is derived from the short black ...
'' oocytes, myricetin is thought to regulate the transport of glucose and fructose through the function of glucose transporter 2 (
GLUT2 Glucose transporter 2 (GLUT2) also known as solute carrier family 2 (facilitated glucose transporter), member 2 (SLC2A2) is a transmembrane carrier protein that enables protein facilitated glucose movement across cell membranes. It is the princi ...
) in sugar absorption. In addition, daily injections of myricetin into rats has been seen to be correlated with increased sensitivity to insulin, indicating the possibility of using a myricetin as treatment or protection against insulin resistance, a frequent cause of diabetes mellitus. In the mouse myoblast cell line known as
C2C12 C2C12 is an immortalized mouse myoblast cell line. The C2C12 cell line is a subclone of myoblasts that were originally obtained by Yaffe and Saxel at the Weizmann Institute of Science in Israel in 1977. Developed for ''in vitro'' studies of myob ...
, treatment with myricetin not only increased glucose uptake, but also enhanced
lipogenesis In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into Adipose tissue, fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in adipose, fat. Lipogenesis encompasses both fatty aci ...
, a result not seen from any of the other bioflavonoids tested. Although myricetin has not been concluded to have more than a neutral effect on humans, it has been used as a form of traditional medicine for diabetes in Northern Brazil and is hypothesized by the Finnish Mobile Clinic Health Examination Survey to potentially be correlated to the lower risk of
Type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
in individuals whose diets included higher than average amounts of myricetin. However, since studies in the United States, such as the Women's Health Study, do not confirm these results, there is doubt of whether or not the difference is risk can actually be accredited to myricetin and is not the result of the inability to fully control other variables such as racial background or inconsistencies in diet between participants. There is also evidence indicating that other characteristics of myricetin, such as its effect against
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
,
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
, and
hyperlipidemia Hyperlipidemia is abnormally high levels of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also use ...
, may be helpful to reduce or even prevent other clinical issues which arise from
diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...
.


Antiatherosclerotic

Antioxidants, including flavonoids such as myricetin, are often touted to reduce the risk of
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
, the hardening of arteries associated with high cholesterol. However, ''in vivo'' studies are lacking and ''in vitro'' studies are contradictory and do not support this claim. This claim is based on myricetin's proposed ability to increase LDL uptake by macrophages, which in theory would protect against atherosclerosis. This theoretical action of myricetin is not supported by experimental data. It is also proposed that myricetin may have the ability as a potent flavonoid antioxidant to prevent LDL oxidation, thus slowing the body's local inflammatory response and delaying the appearance of the first fatty streak and onset of atherosclerosis. Although mechanisms relating to myricetin specifically have not been proven, a diet that is rich in fruits and vegetables, and therefore rich in antioxidants, correlates with a decreased risk of cardiovascular disease, including atherosclerosis.


Neuroprotectant

It has also been shown that myricetin is effective in protecting neurons against oxidative stressors. Researchers have shown that
PC12 cells PC12 is a Cell culture#Common cell lines, cell line derived from a pheochromocytoma of the rat adrenal medulla, that have an Embryonic stem cell, embryonic origin from the neural crest that has a mixture of neuroblast, neuroblastic cells and eosin ...
treated with hydrogen peroxide (H2O2) as an oxidative stressor experience cell death due to
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
. When treated with myricetin, these oxidatively stressed cells displayed statistically significant increased cell survival. It has been suggested that myricetin not only has oxygen radical scavenging abilities, but also inherent, specific cell-survival capacities. Other molecules known for oxygen radical scavenging (
vitamin E Vitamin E is a group of eight compounds related in molecular structure that includes four tocopherols and four tocotrienols. The tocopherols function as fat-soluble antioxidants which may help protect cell membranes from reactive oxygen speci ...
and
boldine Boldine is an alkaloid of the aporphine class that is characteristic of the boldo ''Peumus boldus'', commonly known as boldo (from the Mapuche name ''foḻo''), is a species of tree in the family Monimiaceae and the only species in the genus ...
) did not successfully protect the cell models from oxidative stress and eventual cell death as effectively as myricetin and other biochemically related molecules.


Anti-inflammatory

Myricetin, along with other lipoxygenase- and cyclooxygenase-blocker flavonoids are seen to have significant anti-inflammatory characteristics, demonstrated by their ability to reduce edemas caused by carrageenan and croton oil. The anti-inflammatory nature of myricetin lies in its ability to inhibit the amplified production of
cytokines Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
that occurs during inflammation. Testing on various types of
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
cells, including RAW264.7, as well as on human synovial
sarcoma A sarcoma is a rare type of cancer that arises from cells of mesenchymal origin. Originating from mesenchymal cells means that sarcomas are cancers of connective tissues such as bone, cartilage, muscle, fat, or vascular tissues. Sarcom ...
cells, demonstrated the inhibition of several kinds of cytokines, such as
interleukin-12 Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, helper T cells and human B- lymphoblastoid cells ( NC-37) in response to antigenic stimulation. IL-12 belongs to the family of i ...
and
interleukin-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
, through down-regulation of transcription factors and mediators involved in their production. Other studies suggest that myricetin's anti-inflammatory nature could also potentially be dependent upon interfering in inflammatory signal pathways by inhibiting various kinases and, consequently, the function of
tumor necrosis factor alpha Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
.


Anti-platelet aggregation activity

Exposure to myricetin caused inhibition of rabbit
platelet aggregation Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cytop ...
, induced by
adenosine diphosphate Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound in metabolism and is essential to the flow of energy in living cells. ADP consists of three important structural components: a sugar backbon ...
,
arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...
,
collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
and platelet activating factor (PAF). It inhibited specific receptor binding of PAF in rabbit platelets. The compound was found to be active against
thrombin Prothrombin (coagulation factor II) is encoded in the human by the F2-gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin. Thrombin (Factor IIa) (, fibrose, thrombase, throm ...
and
neutrophil elastase Neutrophil elastase (, ''leukocyte elastase'', ''ELANE'', ''ELA2'', ''elastase 2'', ''neutrophil'', ''elaszym'', ''serine elastase'', subtype ''human leukocyte elastase (HLE)'') is a serine proteinase in the same family as chymotrypsin and has b ...
. In addition, A prostacyclin-stimulated rise in the levels of platelet adenosine 3',5'-cyclic monophosphate (cAMP) was stimulated by myricetin.


Immunomodulatory activities

Myricetin's preclinical
immunomodulatory Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunothera ...
properties are now becoming increasingly widely known. It was discovered that myricetin may prevent
T-lymphocyte T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...
stimulation in a mouse model by binding to anti-CD3 and anti-CD28
monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a Lineage (evolution), cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Mon ...
immobilised on beads. The inhibitory effect of myricetin on T cells, which was described in this study, was explained as being mediated via extracellular production. Through the inhibition of NF-B binding activity, these natural compounds were reported to significantly reduce the lipopolysaccharide (LPS)-induced interleukin (IL)-12 production in mouse main
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s as well as the RAW264.7 monocytic cell-line. Myricetin produced epithelial layer contractile reflexes in separate rat aortic rings at a concentration of 50 M. This substance induces the synthesis of
cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
unbound calcium in cultured
bovine Bovines (subfamily Bovinae) comprise a diverse group of 10 genera of medium to large-sized ungulates, including Bos, cattle, bison, African buffalo, Bubalus, water buffalos, and the four-horned and spiral-horned antelopes. The members of this gro ...
endothelial cells. Myricetin suppressed the release of IL-2 protein from mouse EL-4 T cells that had been stimulated with phorbol 12-myristate 13-acetate (PMA) and
ionomycin Ionomycin is an ionophore and an antibiotic that binds calcium ions (Ca2+) in a ratio 1:1. It is produced by the bacterium '' Streptomyces conglobatus''. It binds also other divalent cations like magnesium and cadmium, but binds Ca2+ preferably. I ...
in a daily dosage approach.


References

{{Purinergics Aromatase inhibitors Flavonols Xanthine oxidase inhibitors Hexols