Does quercetin supplementation affect natural killer activity?
Moreover, quercetin exposure up-regulated the levels of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and its substrate, acetyl-CoA carboxylase (ACC). Treatment of 3T3-L1 adipocytes with quercetin resulted in the induction of apoptosis and a concomitant decrease in ERK and JNK phosphorylation.
Does quercetin inhibit matrix metalloproteinases?
· Mitogen-activated protein kinase (MAPK) inhibitor efficiency based on mutational status—cause of resistance and weak spots. Treatment resistance is a reoccurring problem in the case of MAPK pathway inhibitors. The post-treatment acquirement or selection of tumor cells with new mutations renders the treatment useless.
How does quercetin prevent TNF-α activation?
· Quercetin reduced phorbol calcium ionophore-induced activation of NF-κB and p38 mitogen-activated protein kinase. Quercetin has a significant inhibitory effect on histamine release. The effect of quercetin on histamine secretion from antigen sensitized mast cells was examined by Fewtrell and Gomperts already in 1977 at µM concentrations . Quercetin had an …
How is quercetin metabolized in the body?
· Quercetin and its biologic functions. Quercetin is an ordinary flavonoid that is pervasive in various types of foods and plant. Quercetin glycosides are the dominant flavonoid content that can be found in propolis along with other healthy foods, including fruits and vegetables; particularly onion, broccoli, apple, tea, as well as red wine.
Does quercetin activate AMPK?
To examine the role of quercetin on AMPK activation, we used a synthetic AMPK inhibitor, Compound C, in cancerous cells. As expected, the elevated AMPK activity by quercetin was abrogated (Figure 2C). These results strongly indicate that quercetin induces apoptosis and activates AMPK in MCF-7 breast cancer cells.
What is the mechanism of action of quercetin?
5.1. 2. Mechanism of Action. Several studies in vitro using different cell lines have shown that quercetin inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNF-α) production in macrophages [45] and LPS-induced IL-8 production in lung A549 cells [46].
How is MAPK activated?
The mammalian p38 MAPK families are activated by cellular stress including UV irradiation, heat shock, high osmotic stress, lipopolysaccharide, protein synthesis inhibitors, proinflammatory cytokines (such as IL-1 and TNF-α) and certain mitogens.
Does MAPK have kinase activity?
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase)....Mitogen-activated protein kinase.SearchNCBIproteins2 more rows
Does quercetin interfere with protein absorption?
This study demonstrates that quercetin exhibits dual effects on protein digestion and absorption: 1) suppressing protein digestion by inhibiting trypsin in the intestinal fluid; 2) promoting the intestinal absorption of oligopeptides in the intestinal villi cells.
Does quercetin increase GABA?
The study found that quercetin, as an inhibitor of GABAARs, reduced GABAergic transmission in the prefrontal cortex and alleviated the hyperactivity caused by MK-801.
When is MAPK activated?
ERK1/2 is activated in response to growth factors, hormones and proinflammatory stimuli, while JNK1/2/3 and p38 MAPK α, β, δ, and γ are activated by cellular and environmental stresses, in addition to proinflammatory stimuli (Owens and Keyse, 2007; Kyriakis and Avruch, 2012; Figure 1).
What does the MAPK cascade do?
The MAPK cascades are central signaling pathways that regulate a wide variety of stimulated cellular processes, including proliferation, differentiation, apoptosis and stress response.
What is MAPK signaling pathway?
The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
What genes does MAPK activate?
MAPK pathways activation is a mechanism for causing early-response gene expression by controlling the activities of several transcription factors. Activated MAPKs translocate to the nucleus, where they phosphorylate target transcription factors, including AP-1, NF-κB, and p53.
What activates a kinase?
Important subgroups are the kinases of the ERK subfamily, typically activated by mitogenic signals, and the stress-activated protein kinases JNK and p38. While MAP kinases are serine/threonine-specific, they are activated by combined phosphorylation on serine/threonine and tyrosine residues.
How does an activated receptor tyrosine kinase RTK activate a kinase cascade?
In particular, the binding of a signaling molecule with an RTK activates tyrosine kinase in the cytoplasmic tail of the receptor. This activity then launches a series of enzymatic reactions that carry the signal to the nucleus, where it alters patterns of protein transcription.
What is the MAPK pathway?
The mitogen-activated protein kinase (MAPK) pathway is an important bridge in the switch from extracellular signals to intracellular responses. Alterations of signaling cascades are found in various diseases, including cancer, as a result of genetic and epigenetic changes. Numerous studies focused on both the homeostatic and the pathologic conduct of MAPK signaling; however, there is still much to be deciphered in terms of regulation and action models in both preclinical and clinical research. MAPK has implications in the response to cancer therapy, particularly the activation of the compensatory pathways in response to experimental MAPK inhibition. The present paper discusses new insights into MAPK as a complex cell signaling pathway with roles in the sustenance of cellular normal conduit, response to cancer therapy, and activation of compensatory pathways. Unfortunately, most MAPK inhibitors trigger resistance due to the activation of compensatory feed-back loops in tumor cells and tumor microenvironment components. Therefore, novel combinatorial therapies have to be implemented for cancer management in order to restrict the possibility of alternative pathway activation, as a perspective for developing novel therapies based on integration in translational studies.
What is MAPK inhibitor efficiency?
Mitogen-activated protein kinase (MAPK) inhibitor efficiency based on mutational status—cause of resistance and weak spots. Treatment resistance is a reoccurring problem in the case of MAPK pathway inhibitors. The post-treatment acquirement or selection of tumor cells with new mutations renders the treatment useless. In the case of KRAS, BRAF, and MEK inhibitors, mutations in any of these two components can determine therapeutic resistance and relapse. Targeting ERK can become a true Achilles heel in treating cancers with MAPK signaling alterations, as ERK inhibitors target specifically downstream of the signaling cascade, with no regard of the mutational status of the upstream components (e.g., KRAS and BRAF) (KRAS: Kirsten rat sarcoma viral oncogene homolog; BRAF: B-Raf proto-oncogene serine/threonine kinase; ERK:extracellular regulated MAP kinase).
What is the effect of PTEN mutations on cancer?
The PTEN mutational status affects the response to combined therapy based on MEK and mTOR inhibitors in cancer [ 37 ], a fact that needs to be further investigated in the context of personalized treatment. PTEN proved to be a vital factor for promoting the response to MAPK inhibitors in myeloid leukemia, as PTEN regulates EGR1 expression and contributes to the cytokine sensitivity when treated with MAPK inhibitors [ 38 ]. PTEN loss and activation of KRAS (Kirsten rat sarcoma viral oncogene homolog) are correlated with cytoskeleton alteration, and they act as possible therapeutic targets which would allow testing of new compounds for more specific targeted therapies, having the capacity to modulate the PI3K and RAS/MAPK pathways [ 39 ]. To further consolidate this idea, experimental data on normal breast cells showed that PTEN inhibition is related to the activation of KRAS, with an impact on PI3K/AKT/mTOR and RAS/MAPK signaling, confirming the interconnection between the cellular pathways [ 39 ]. The loss of PTEN, leading to RAS/MAPK activation, was proven to be involved in EMT (epithelial–mesenchymal transition), a mechanism that sustains invasions and metastasis. Therefore, the inhibition of RAS/MAPK signaling using PD325901, an MEK inhibitor, was correlated with a reduced metastatic progression as an effect of transplantation with stem/progenitor cells [ 40 ].
What are some examples of small molecules tested as mitogen-activated protein kinase (MAPK)
Examples of small molecules tested as mitogen-activated protein kinase (MAPK) inhibitors on in vitro and in vivo studies. EGFR—epidermal growth factor receptor.
What is the signaling cascade of MAPK?
The framework of a signaling cascade such as MAPK is complex, with many interacting pathways and constant crosstalk, which are each subjected to fine-tuning and switch-like activations of regulatory factors ( Figure 1 ). As an overview, the MAPK pathways converge in the amplification of key molecules that sustain cell proliferation, growth, and survival processes [ 17, 18 ]. The outline of the MAPK signaling cascade consists of the interaction of one or more growth factors (GFs) with their specific growth factor receptors (GFRs). Generally, GFs bind and activate transmembrane glycoproteins of the receptor tyrosine kinase (RTK) family and activate the signal transduction cascade, followed by signal transduction through cytosolic intermediates, and finally the transcription/translation regulation of effector genes [ 19 ]. These are mainly represented by growth factor receptors, which promote, following their activation, the downstream signal transduction [ 19 ]. One such example consists of the epithelial growth factor (EGF), which targets its high-affinity membrane receptor (EGFR: epidermal growth factor receptor) [ 20 ].
What is the role of the mitogen-activated protein kinase in cancer?
The mitogen-activated protein kinase (MAPK) is one such complex interconnected signaling cascade with frequent involvement in oncogenesis, tumor progression, and drug resistance. The MAPK family consists of a large number of kinases altered in cancers and against which many targeted therapies were developed. Resistance to MAPK inhibitors is a current problem, particular due to the high degree of interactions and possible compensatory responses. Thus, in this review, we discuss the many implications of the MAPK pathways in cancer, with a particular focus on the regulation of tumor signaling through emphasis of MAPK crosstalk with key signaling pathways in pathological conditions.
Why is the mutational landscape important?
The description of the mutational landscape in a complex signaling cascade such as MAPK is essential when attempting to outline effective therapies that would target a specific mutated component of the pathway ( Figure 3 ). This is the main direction in which therapies based on inhibitory molecules were developed. Efficient targeting of the aberrantly activated MAPK pathway in cancer is one of the most explored therapeutic approaches. Due to the in-depth characterization of its signaling intermediates, there were major improvements in the treatment of melanoma or lung cancer with the use of generally termed MAPK inhibitors.
What is quercetin used for?
Quercetin is the great representative of polyphenols, flavonoids subgroup, flavonols. Its main natural sources in foods are vegetables such as onions, the most studied quercetin containing foods, and broccoli; fruits (apples, berry crops, and grapes); some herbs; tea; and wine. Quercetin is known for its antioxidant activity in radical scavenging and anti-allergic properties characterized by stimulation of immune system, antiviral activity, inhibition of histamine release, decrease in pro-inflammatory cytokines, leukotrienes creation, and suppresses interleukin IL-4 production. It can improve the Th1/Th2 balance, and restrain antigen-specific IgE antibody formation. It is also effective in the inhibition of enzymes such as lipoxygenase, eosinophil and peroxidase and the suppression of inflammatory mediators. All mentioned mechanisms of action contribute to the anti-inflammatory and immunomodulating properties of quercetin that can be effectively utilized in treatment of late-phase, and late-late-phase bronchial asthma responses, allergic rhinitis and restricted peanut-induced anaphylactic reactions. Plant extract of quercetin is the main ingredient of many potential anti-allergic drugs, supplements and enriched products, which is more competent in inhibiting of IL-8 than cromolyn (anti-allergic drug disodium cromoglycate) and suppresses IL-6 and cytosolic calcium level increase.
What is the endogenous antioxidant ability of quercetin?
Endogenous antioxidant ability of quercetin modifies the range of cellular injury during the allergic damage that is caused by free radicals. Enzymes, such as repair and de novoones (lipases, DNA repair enzymes, proteases and transferases), act as the third line of defense by repairing damage and reconstituting membranes [4,69].
Is quercetin a phenolic compound?
Quercetin is a frequently studied phenolic compound due to its known great antioxidant properties. Its flavonoid structure, 2,3 double bound in conjunction with 4-oxo bond in the C ring of quercetin, allows electron delocalization from the B ring and shows extensive resonance. This results in the significant efficiency for radical scavenging [66]. Therefore, quercetin has a structure that is responsible for higher antioxidant activity effectiveness than the structure of anthocyanins.
What are the glycosides in tea?
Black tea and oolong tea, both fermented tea types, have the highest content of quercetin types of flavonol glycosides (50%–52% in oolong tea and 54%–71% in black tea, respectively); green tea manufactured without the process of fermentation has a higher content of kaempferol glycosides, while quercetin represents about 18%–38% of all flavonol glycosides [62]. The predominant quercetin glycosides in black tea are quercetin glucoside, rutinoside (rutin), and galactoside; minor representatives are quercetin dirhamnoglucoside and rhamnogalactoside; and quercetin rhamnodiglucoside is present in the lowest levels. Oolong tea contains mainly quercetin glucorhamnoglucoside, rutinoside, rhamnogalactoside and quercetin dirhamnoglucoside. Quercetin rhamnogalactoside, rhamnodiglucoside and quercetin glucorhamnoglucoside are principal glycosides presented in green tea [62]. The main quercetin forms of green pu-erh tea comprise two constituents, quercetin 3-rhamnosylgalactoside and 3-glucoside. White tea has as predominant flavonol quercetin 3-glucosylrutinoside [63]. There is about 15–35-times higher content of rutin than quercetin [21].
Is quercetin in apples?
In apples, another great quercetin source , there are well studied antioxidant compounds such as quercetin-3-galactoside, quercetin-3-glucoside, and quercetin-3-arabinoside [33,41] in the content range of 21–72 mg/kg; quercetin-3-rhamnoside [52]; and quercetin-3-rutinoside [28]. Quercetin conjugates are present entirely in the apple peels [28,53]. Due to the presence of more antioxidants such as quercetin in the apple peel than in the flesh, the apple peels may be considered to have higher antioxidant capacity and also bioactivity [54]. In apples, other dietary quercetin glycosides such as quercetin galactosides are also found [34].
Is quercetin a plant food?
The quercetin content of plant foods differs depending on the cultivars or cultivation conditions [25,29,30]. Its content has been shown to also be dependent on light exposure [31].
Is quercetin a glycosidic?
Quercetin is present in plants in many different glycosidic forms. It is usually found in conjugated forms with sugars such as glucose, galactose and rhamnose [28]. The prevalent forms are quercetin conjugated with one or two glucose molecules, such as isoquercetin; and quercetin conjugated with rutinose such as quercetin rutinoside—rutin. However, the aglycone form of quercetin occurs in much lower levels in foods. Different quercetin forms represent 60%–75% of flavonoid intake [12].
Where is the Center for Biochemistry and Nutrition in Metabolic Diseases?
5Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. of Iran
Does quercetin cause cancer?
In vitro and in vivo experiments have revealed that quercetin possesses a cytotoxic impact on ovarian cancer cells. Despite obtaining good results both in vitro and in vivo, few clinical studies have assessed the anti-cancer effects of quercetin particularly in the ovarian cancer.
Is doxorubicin a chemotherapeutic agent?
Doxorubicin is a chemotherapeutic agent that used in various cancer including ovarian, thyroid, breast, and lung cancer but a notable unfavorable effect such as cardiotoxicity limits its use [100]. To overcome this limit, scientific used quercetin as a chemosensitizer in combination with doxorubicin.
Is quercetin an anti-proliferative agent?
It seems that quercetin plays an important role as an anti-proliferative and anticancer agent and also stimulates apoptosis (Fig. 3) [52]. Numerous studies probed the influence of isolated quercetin compound in different cancer cell lines.
Is quercetin a flavonoid?
Quercetin and its biologic functions. Quercetin is an ordinary flavonoid that is pervasive in various types of foods and plant.
Does quercetin help with ovarian cancer?
According to the previous literature, consuming vegetables that are rich in quercetin has been associated with lower risks of ovarian cancer [21]. Similarly, consuming fruits with high levels of quercetin, including apples as well as citrus or their juice can decrease occurrence of ovarian cancer [22].
Is quercetin a phytochemical?
In this regard, quercetin, which can be extensively observed in daily foods including nuts, teas, vegetables, different plants, and in general the daily dietary program of people, is a common phytochemical [6]. Moreover, this supplementary agent is commercially accessible, while its oral application at a dose of 1 g per day is safe enough and can be absorbed up to 60% [7]. An extensive range of pharmacologic activities has been reported for quercetin, including anti-oxidant, anti-diabetes, anti-inflammation, as well as anti-proliferation [8, 9]. Quercetin, 2-(3,4-dihy-droxyphenyl)-3,5,7-trihydroxy4H-chromen-4-one includes two benzene rings named A and B, and joined through a 3-carbone heterocyclic pyrone one [9]. Since two antioxidant pharmacophores are present in the structure of quercetin, it can largely remove free radicals and join to transitional metal ions [9]. Moreover, catechol along with the OH group presenting at the position C3 in the structure of quercetin is an ideal arrangement to scavenge free radicals [9]. This agent is a pental-hydroxyl-flavonol consisting of 5 hydroxyl groups on the flavonol structure at 3, 30, 40 5, and 7 position carbons. Replacement of various functional groups leads to different biochemical as well as pharmacologic properties of quercetin [10].
What is the main source of quercetin?
Quercetin is the great representative of polyphenols, flavonoids subgroup, flavonols. Its main natural sources in foods are vegetables such as onions, the most studied quercetin containing foods, and broccoli; fruits (apples, berry crops, and grapes); some herbs; tea; and wine.
What is quercetin found in?
Its main natural sources in foods are vegetables such as onions, the most studied quercetin containing foods, and broccoli; fruits (apples, berry crops, and grapes); some herbs; tea; and wine. Quercetin is known for its antioxidant activity in radical scavenging ...
Which is more effective in inhibiting IL-8 than cromolyn?
Plant extract of quercetin is the main ingredient of many potential anti-allergic drugs, supplements and enriched products, which is more competent in inhibiting of IL-8 than cromolyn (anti-allergic drug disodium cromoglycate) and suppresses IL-6 and cytosolic calcium level increase.
Is quercetin an anti-allergic?
Quercetin and Its Anti-Allergic Immune Response. Quercetin is the great representative of polyphenols, flavonoids subgroup, flavonols. Its main natural sources in foods are vegetables such as onions, the most studied quercetin containing foods, and broccoli; fruits (apples, berry crops, and grapes); some herbs; tea; and wine.
Is quercetin an anti-inflammatory?
All mentioned mechanisms of action contribute to the anti-inflammatory and immun omodulating properties of quercetin that can be effectively utilized in treatment of late-phase, and late-late-phase bronchial asthma responses, allergic rhinitis and restricted peanut-induced anaphylactic reactions.
Is Quercetin a compound?
Quercetin is a most promising compound for disease prevention and therapy; however, many of the effects still need confirmation by human intervention trials. Quercetin is a most promising compound for disease prevention and therapy ; however, many of the effects still need confirmation by human intervention trials.
Does quercetin help with obesity?
Together with its antithrombotic and anti-inflammatory effects, the latter mainly mediated through the inhibition of cytokines and nitric oxide, quercetin is a candidate for preventing obesity-related diseases. Most exiting are the findings that quercetin enhances physical power by yet unclear mechanisms.
How does oxidative stress affect aging?
Oxidative stress has been implicated in aging and age-related diseases. Mounting evidence suggests that natural compounds with antioxidant properties exert health beneficial effects. The antioxidant activities of polyphenols have been attributed to ROS scavenging. However, a number of recent studies suggest that they also act through modulation of cell signaling pathways that increase cellular defense mechanisms. This phenomenon, known as xenohormesis, refers to sensing in one organism (yeast in this study) of a compound produced in another specie (plant) in response to environmental stress, leading to the induction of a defense response that increases its chances of survival [60]. We have previously shown that quercetin, the most common flavonol in the diet, increases oxidative stress resistance in yeast cells by scavenging free radicals, maintaining the redox homeostasis, and preventing protein carbonylation and lipid peroxidation [33]. Aiming to characterize genome-wide changes in gene expression induced by quercetin in yeast, a microarray analysis was performed. The results obtained show that quercetin down regulated a significant number of genes belonging to RNA metabolism and ribosome biogenesis categories. This cellular adaptation has been observed in response to multiple stress conditions [61] and is beneficial since it spares energy resources for cellular processes other than ribosome biosynthesis (the most energy consuming cellular process).
Is quercetin a flavonol?
Quercetin is a naturally occurring flavonol with antioxidant, anticancer and anti-ageing properties. In this study we aimed to identify genes differentially expressed in yeast cells treated with quercetin and its role in oxidative stress protection.
Does quercetin affect glucose metabolism?
Most of these genes ( HXK1, GLK1, PGM2, ENO1, PYK2, PYC1 and PYC2) are under catabolite repression and their expression increases in response to glucose depletion [36] – [41]. Under these conditions, they function in the gluconeogenesis pathway that is activated for glucose production. Consistent with quercetin inducing a glucose restriction-like phenotype, the HXT2 gene, which encodes a high-affinity glucose transporter induced by low levels of glucose [42], and genes that encode for the Ira1p and Ira2p GTPase-activating proteins ( Table 1) were up regulated. These proteins negatively regulate RAS by converting it from the GTP- to the GDP-bound inactive form, which is required for reducing cAMP levels under nutrient limiting conditions, preventing the activation of the glucose-regulated cAMP-dependent protein kinase signaling pathway [43].
Does quercetin affect the cell wall?
Quercetin also increased the expression of genes encoding proteins that exhibit a cortical patch membrane localization pattern ( Table 1 ), which are involved in the regulation of actin cytoskeleton, endocytosis, cell wall biogenesis and viability following starvation or osmotic stress [54], [55]. Moreover, quercetin up regulated several genes that encode proteins related to the cell wall, such as Sed1p (cell wall glycoprotein), Yps1p and Yps3p (aspartic proteases), and Fks1p (1,3- β-D-glucan synthase) ( Table 1 ). Cell wall biogenesis and maintenance are regulated by the CWI pathway, a Pkc1p-modulated MAPK cascade [56]. The MAPK module is composed of the MAPK kinase kinase Bck1p, a pair of redundant MAPK kinases (Mkk1p and Mkk2p), and the MAPK Slt2p/Mpk1p. To test if quercetin activates this pathway, phospho-Slt2p levels were analyzed by Western blotting, using an anti-phospho-p44/42 antibody that detects dually phosphorylated Slt2p, the active form of this MAPK. Phospho-Slt2p levels were significantly increased in cells treated with quercetin for 15 and 60 min ( Figure 5A ). We also characterized changes in Rlm1p, a transcription factor regulated by Slt2p [57], by measuring β-galactosidase activity in cells expressing a LacZ reporter under the control of Rlm1p ( RLM1 - lacZ ). Consistent with an induction of the Rlm1p-reporter, β-galactosidase activity increased 50% in cells treated with quercetin ( Figure 5B ). The activation of the CWI pathway is important for oxidative stress resistance [58] and increases cellular resistance to cell wall perturbing agents, such as zymolyase, a lytic enzyme that degrades β1,3-glucans, the main component of cell wall. Consistent with Slt2p activation, quercetin increased zymolyase resistance ( Figure 5C ). Moreover, inactivation of SLT2 gene decreased the protective effect of quercetin against H 2 O 2 ( Figure 5D ). These results indicate that quercetin increases H 2 O 2 resistance through activation of the CWI pathway.
