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At least 19 recordsLinked to original sources
PubMed2026

An Arabidopsis Protein-Flavonoid Interactome Identifies Peroxiredoxin A as a Candidate for Flavonoid Action in Chloroplasts.

The ability of phytochemicals to act as small molecule effectors of protein function is a largely overlooked dimension of plant biochemistry. This is particularly true for the ubiquitous flavonoids where, despite abundant examples of functional interactions with human proteins, biological activities in plants are primarily attributed to ROS scavenging. We used affinity capture to explore the protein interactome of the flavonoid glycoside, rutin, in Arabidopsis seedlings. Unexpectedly, the 397 high-confidence candidates included numerous proteins associated with chloroplasts, where flavonoids are present at exceedingly low levels. Intriguingly, several identified targets are conserved with known flavonoid-interacting proteins in mammals, where the bioavailability of flavonoids is similarly low. Using one of these, the Arabidopsis plastidial 2-cys peroxiredoxin A, as a test case, this study substantiated the potential of affinity proteomics for identifying novel protein targets of phytochemicals and suggests that flavonoids modulate protein function in plants to a larger extent than previously suspected.

Arabidopsis↗
PubMed2026

Functional Characterization of a Novel Flavonoid O-methyltransferase From Polar Pedobacter sp. PAMC26386 and Bioactivity Assessment of Flavonoids.

Flavonoid O-methyltransferases (OMTs) catalyze the methylation of flavonoid hydroxyl groups, enhancing structural diversity and biological activity. In this study, we identified and characterized a novel Class I flavonoid OMT from the Antarctic bacterium Pedobacter sp. PAMC26386. Despite originating from a cold-adapted organism, the enzyme exhibited high catalytic activity at 55 °C and a strong preference for Co²⁺ as a cofactor. Sequence and phylogenetic analyses confirmed its classification as a flavonoid-specific OMT and revealed conserved motifs for S-adenosyl-L-methionine (SAM) binding and metal coordination. The enzyme accepted a wide range of flavonoid substrates, with quercetin and fisetin showing the highest activities. Kinetic analysis indicated greater substrate affinity for quercetin (Km = 36.55 µM) than for fisetin (Km = 49.41 µM). Whole-cell biotransformation using recombinant Escherichia coli C41 co-expressing the OMT and metK enabled efficient intracellular methylation, yielding 62.5 mg L⁻¹ of methylated quercetin and 55.5 mg L⁻¹ of 3'-O-methyl fisetin. The predicted methylation site at the 3'-hydroxyl of fisetin, determined by molecular docking, was confirmed by NMR spectroscopy. Notably, the previously reported 3'-O-methyl fisetin showed enhanced in vitro anticancer activity against mouse breast cancer cells and selectively improved antimycobacterial activity against Mycobacterium tuberculosis compared to the parent compound. To our knowledge, this study is among the first to report the enzymatic production of 3'-O-methyl fisetin using a polar microbial OMT that is optimally active at elevated temperatures in the presence of Co²⁺. The increased bioactivity compared to the parent compounds highlights the potential of this OMT as a biocatalyst for the sustainable production of pharmaceutically relevant methylated flavonoids.

Flavonoids↗
PubMed1991

Induction of sister-chromatid exchanges (SCE), polyploidy, and micronuclei by plant flavonoids in human lymphocyte cultures. A comparative study of 19 flavonoids.

Nineteen naturally occurring flavonoids were studied with regard to their SCE-inducing potency and their capability of inducing polyploidy and micronuclei in human lymphocyte cultures. The cells were treated for a period of 48 h. The flavone C-glycosides, vitexin and orientin, exhibited a moderate SCE-inducing activity, whereas the other compounds displayed only weak effects or were inactive. Polyploidy was induced by procyanidins consisting of 3 or 4 flavanol units and to a lesser extent by flavone, flavonol, and anthocyanidin aglycones. The aglycones as well as the C-glycosides and the O-glycosides, spiraeoside and luteolin-7-glucoside, were more or less active in inducing micronuclei in the lymphocytes. The flavonol O-glycosides, rutin and hyperoside, and the monomeric and dimeric flavanols failed to produce any genotoxic effects. The results are discussed with respect to a possible structure-activity relationship.

Flavonoids↗
PubMed1992

Effects of flavonoids on immune and inflammatory cell functions.

No doubt can remain that the flavonoids have profound effects on the function of immune and inflammatory cells as determined by a large number and variety of in vitro and some in vivo observations. That these ubiquitous dietary chemicals may have significant in vivo effects on homeostasis within the immune system and on the behavior of secondary cell systems comprising the inflammatory response seems highly likely but more work is required to strengthen this hypothesis. Ample evidence indicates that selected flavonoids, depending on structure, can affect (usually inhibit) secretory processes, mitogenesis, and cell-cell interactions including possible effects on adhesion molecule expression and function. The possible action of flavonoids on the function of cytoskeletal elements is suggested by their effects on secretory processes. Moreover, evidence indicates that certain flavonoids may affect gene expression and the elaboration and effects of cytokines and cytokine receptors. How all of these effects are mediated is not yet clear but one important mechanism may be the capacity of flavonoids to stimulate or inhibit protein phosphorylation and thereby regulate cell function. Perhaps the counterbalancing effect of cellular protein tyrosine phosphatases will also be found to be affected by flavonoids. Some flavonoid effects can certainly be attributed to their recognized antioxidant and radical scavenging properties. A potential mechanism of action that requires scrutiny, particularly in relation to enzyme inhibition, is the redox activity of appropriately configured flavonoids. Finally, in a number of cell systems it seems that resting cells are not affected significantly by flavonoids but once a cell becomes activated by a physiological stimulus a flavonoid-sensitive substance is generated and interaction of flavonoids with that substance dramatically alters the outcome of the activation process.

Animals↗
PubMed2026

ARR1 and ARR12 negatively regulate arsenic stress tolerance by controlling flavonoid metabolism in Arabidopsis.

ARR1/12-mediated cytokinin signaling negatively regulates the accumulation of glycosylated flavonoids, thereby increasing plant susceptibility to As(III) stress. Cytokinins negatively regulate arsenic stress tolerance in plants through cytokinin-signaling type-B Arabidopsis response regulators (B-ARRs), specifically ARR1 and ARR12. However, the mechanism by which cytokinin signaling regulates plant metabolite dynamics, particularly antioxidant flavonoids, in response to arsenic toxicity remains largely unknown. Here, we hypothesized that ARR1/12-mediated cytokinin signaling modulates flavonoid metabolism to regulate arsenite [As(III)] tolerance. By comparing the global metabolic changes in roots of the arr1 12 double mutant (rD) and wild-type (WT) plants, we found that As(III) stress globally reduced metabolite abundance in WT roots. Importantly, the rD mutant accumulated significantly more flavonoids, most in glycosylated forms, than WT under As(III) exposure, which was supported by the specific upregulation of UDP-glycosyltransferase genes involved in flavonoid glycosylation. Accordingly, exogenous application of the glycosylated quercitrin-enhanced As(III) tolerance in WT roots, strengthening that the increase of glycosylated flavonoids in rD roots was beneficial for plant survival under As(III) exposure. Our data collectively strongly support that the increased glycosylation of flavonoids in the rD mutant improves their antioxidant functionality, thereby enhancing the As(III) stress tolerance. This study provides a new insight into the negative role of cytokinin signaling in repressing glycosylated flavonoid accumulation, causing increased susceptibility of plants to As(III) stress. Manipulation of cytokinin signaling or flavonoid glycosylation is, therefore, a promising approach for heavy metal stress mitigation in crops.

Arabidopsis↗
PubMed1992

Evolution of regulation of steroid-mediated intercellular communication in vertebrates: insights from flavonoids, signals that mediate plant-rhizobia symbiosis.

Various flavonoids, such as genistein, luteolin, and coumestrol, have actions in mammals that are mediated by binding either to classical estrogen receptors or to type II receptors, which also bind estrogen. These actions are of intense interest because they may be the basis for the protective actions of plants against certain cancers, such as breast cancer. The biological activity of flavonoids in mammals raises some questions. Is the hormonal action of flavonoids "an accident" derived from their phenolic groups and general hydrophobicity, which gives them some properties in common with estrogens? Or do flavonoids regulate gene transcription in other organisms? And, if so, is there a connection between their actions in these organisms and in mammals? Some answers to these questions are provided by the actions of plant-derived flavonoids in regulating gene transcription in rhizobia, bacteria that form nitrogen-fixing nodules in the roots of legumes, which has several interesting similarities with steroid-mediated actions in vertebrates. First, there is specificity in the actions of flavonoids in rhizobia; oxidation or reduction of the flavonoid or removal of a hydroxyl group can alter its biological activity. Moreover, some flavonoids are anti-inducers functioning like steroid antagonists to negate the actions of inducers. Also there are sequence similarities between various steroid metabolizing enzymes and proteins found in rhizobia, which indicates that these proteins are derived from a common ancestor. For example, 17 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone a C17 on estrogens and androgens, 11 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone at C11 of glucocorticoids, and 3 alpha,20 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone at C20 of corticosteroids, are homologs of proteins found in rhizobia. Thus, the binding of flavonoids to vertebrate proteins may represent an evolutionary linkage between the actions of steroids in mammals and communication between plants and rhizobia.

Animals↗
PubMedDate not supplied

[Flavonoids: antithrombotic agents or nutrients?].

Flavonoids are a vast group of natural substances, but their pharmacological properties have not all been explored. The term flavonoid is used at large to designate a series of more than 4,000 molecules, which in fact can have very heterogenous molecular structures. We have shown that some flavonoids are good inhibitors of cyclic nucleotide phosphodiesterase (PDE). The most active PDE inhibitors among the flavonoids were also good inhibitors of the aggregation of human platelets in vitro. This suggests that flavonoids could serve as a template for the development of new anti-platelet drugs. However, a direct extrapolation of our experimental results to possible therapeutical use of flavonoid-containing medicinal plant extracts is not possible. The metabolic fate of these plant flavonoids is poorly understood, and their absence of toxicity has not always been clearly demonstrated. Flavonoids are also present in a regular diet in significant amounts. The role of these dietary flavonoids in the prevention of thrombotic diseases or atherosclerosis should also be investigated.

Fibrinolytic Agents↗
PubMed2026

Progressive salinity drives flavonoid branch reprogramming in Anoectochilus roxburghii.

Flavonoids play critical roles in plant adaptation to abiotic stress; however, how salt stress modulates metabolic flux distribution within flavonoid branches remains poorly understood, particularly in non-model medicinal plants. Here, we integrated targeted metabolomics, transcriptomics, and proteomics to examine flavonoid regulation in Anoectochilus roxburghii under 0, 50, 100, and 200 mmol·L- 1 NaCl. Metabolite profiling showed that salinity reshaped flavonoid composition rather than uniformly increasing flavonoid abundance. A metabolite-derived branch bias index (MI), representing the balance between reductive branch metabolites and flavonol products, increased under salt treatment, peaked at 100 mmol·L- 1 NaCl, and declined at 200 mmol·L- 1, indicating maximal branch bias under moderate stress followed by partial rebalancing under severe stress. Transcriptomic analysis showed induction of upstream phenylpropanoid and flavonoid entry genes, including PAL, 4CL, and CHS, whereas F3H was suppressed and FLS showed no induction. Furthermore, several short-chain dehydrogenase/reductase homologs (IFR-like SDR homologs) were upregulated, and the transcript-derived reductive branch index (EI) increased progressively across the salt gradient. EI was positively associated with MI, although the relationship was not strictly proportional under severe stress (200 mmol·L- 1 NaCl). Proteomic profiling further provided supportive evidence for sustained activation of upstream flavonoid biosynthesis, such as salt-induced accumulation of chalcone synthase (CHS) protein, complementing the transcriptomic and metabolomic datasets. Together, these results indicate that salt stress reorganizes flavonoid metabolism in A. roxburghii through persistent upstream activation and branch-specific regulation, favoring the reductive branch under moderate salinity.

Orchidaceae↗
PubMed1991

Effect of myricetin and other flavonoids on the liver plasma membrane Ca2+ pump. Kinetics and structure-function relationships.

Thirty-three different flavonoids were screened for their ability to influence ATP-dependent Ca2+ uptake by rat liver plasma membrane vesicles. Nine of the flavonoids, at a concentration of 100 microM inhibited Ca2+ uptake by more than 20%. The remaining 24 flavonoids exhibited little or no effect. The relative order of potency of the more biologically active flavonoids was myricetin greater than butein greater than phloretin = luteolin greater than eriodictyol = silybin. Myricitrin and phloridzin, the glycosides of myricetin and phloretin, respectively, had no effect. The degree of inhibition caused by myricetin was concentration dependent and was also affected by the preincubation time. After 10 min of preincubation, 52 microM myricetin lowered the initial rate of 45Ca uptake by 50%. The inhibition by myricetin was non-competitive with respect to Mg-ATP and of a mixed type with respect to Ca2+. At a concentration of 100 microM, myricetin had no effect on several plasma membrane enzymes such as 5'-nucleotidase, alkaline phosphatase and a Ca2(+)-activated ATPase but inhibited K(+)-dependent p-nitrophenyl phosphatase by 83%. The ATP-dependent Ca2+ transport systems located on the plasma membrane or endoplasmic reticulum derived from other tissues were also inhibited by myricetin. Analysis of the structure-activity relationship revealed that lipid solubility and polyhydroxylation particularly at positions 5,7,3' and 4' of the flavonoid ring structure enhanced the ability of the flavonoid to inhibit Ca2+ uptake. The results suggest that inhibition of Ca2+ transport activity probably involves the interaction of the phenolic groups of the flavonoid with the Ca2+ transporting protein.

Adenosine Triphosphate↗
PubMed1992

Inhibition of glutathione reductase by flavonoids. A structure-activity study.

A structure-activity study of fourteen chemically related flavonoids was conducted to evaluate their abilities to inhibit glutathione reductase (GR). By comparing the I50 values of flavonoids from different classes possessing an identical hydroxyl configuration, we determined the following order of potency for inhibition of GR: anthocyanidin > dihydroflavonol = chalcone > flavonol > catechin. Enzyme inhibition by delphinidin chloride and myricetin was partially prevented in a N2 atmosphere which implicates a role for oxygen in the mechanism of inhibition. To determine the role of oxygen species in enzyme inhibition, GR was preincubated with either mannitol, diethylenetriaminepenta-acetic acid (DETAPAC), superoxide dismutase (SOD), catalase (CAT), or SOD and CAT prior to assays for enzyme inhibition by flavonoids. Enzyme inhibition by delphinidin chloride and myricetin was suppressed by the addition of SOD, suggesting that superoxide (O2-.) is involved. However, inhibition by quercetin and morin was not sensitive to antioxidants. To further investigate the role of O2-. in GR inhibition, a superoxide generating system was utilized in the presence and absence of flavonoid. The O2-. generating system failed to inhibit GR in the absence of flavonoid but enhanced the inhibition by myricetin, indicating that the O2-. did not directly inhibit GR but reacted directly with certain flavonoids to form a reactive intermediate which, in turn, inhibited GR. These findings suggest that the mechanism of inhibition of GR by flavonoids is complex and may have oxygen-dependent and oxygen-independent components.

Antioxidants↗
PubMed1992

Effect of various flavonoids on lysosomes subjected to an oxidative or an osmotic stress.

When a light mitochondrial fraction (L fraction) of rat liver is incubated in the presence of an oxygen free radical generating system (xanthine-xanthine oxidase), the free activity of N-acetylglucosaminidase (NAGase) increases as a result of the deterioration of the lysosomal membrane. Various flavonoids are able to prevent this phenomenon, others are ineffective. Comparative activity studies suggest the importance of the presence of two OH groups in orthosubstitution in the B ring and of an OH in the 3 position. Flavan-type flavonoids behave like their related flavonoids; d-catechin also opposes lysosome disruption. Kaempferol, quercetin, 7,8-dihydroxyflavone and d-catechin inhibit lipoperoxidation occurring in an L fraction incubated with the xanthine oxidase system as ascertained by malondialdehyde (MDA) production. For kaempferol and quercetin, such an inhibition parallels the prevention of NAGase release; this is not the case for the two other compounds where inhibition of NAGase release takes place at a flavonoid concentration lower than that required to oppose MDA production. Morphological observations performed on purified lysosomes confirm the biochemical results. Some flavonoids are also able to prevent release of NAGase caused by the incubation of an L fraction in isoosmotic glucose. Only flavone and hydroxyflavones are effective. It is proposed that the protective effect of flavonoids on lysosomes subjected to oxygen free radicals does not only originate from their scavenger and antilipoperoxidant properties; a more direct action on lysosomal membrane making it more resistant to oxidative aggression has to be considered. The prevention by some flavonoids of lysosome osmotic disruption in isoosmotic glucose could be the result of an inhibition of glucose translocation through the lysosomal membrane.

Acetylglucosaminidase↗
PubMed2026

Comparative metabolomic and transcriptomic profiling of flavonoid diversity and antioxidant capacity in three Isatis species.

Flavonoids are key bioactive compounds in plants with significant health benefits. This study employs an integrated multi-omics approach to investigate flavonoid diversity and antioxidant capacity across three Isatis species: I. oblongata, I. tinctoria, and I. indigotica. Metabolomic profiling identified 200 flavonoids, with glycosides being the most abundant class. I. tinctoria exhibited the highest total flavonoid content and antioxidant activity, strongly correlated with the accumulation of 53 core differential flavonoid metabolites, most of which were glycosylated derivatives. Transcriptomic analysis revealed coordinated upregulation of phenylpropanoid pathway genes and specific UDP-glycosyltransferases (UGTs) in I. tinctoria, providing a genetic basis for its enhanced glycoside production. The study establishes a clear genotype-metabolite-phenotype linkage, highlighting glycosylation as a key mechanism underlying flavonoid-driven antioxidant superiority in Isatis. Although the current evidence is primarily correlative, the consistent and strong associations across independent transcriptomic, metabolomic, and antioxidant datasets provide a robust foundation for this conclusion. These findings offer new insights into the metabolic evolution and regulatory networks of flavonoids, with implications for breeding and metabolic engineering of high-value medicinal plants.

Flavonoids↗
PubMed1991

Inhibition of wheat embryo calcium-dependent protein kinase and avian myosin light chain kinase by flavonoids and related compounds.

Avian myosin light chain kinase (MLCK) is inhibited by a range of plant-derived flavonoids. Maximal inhibition requires 2,3-unsaturation and polyhydroxylation of two of the three flavonoid rings. Phosphorylation of a synthetic myosin light chain-related peptide by wheat embryo Ca(2+)-dependent protein kinase (CDPK) is also inhibited by a range of flavonoids but phosphorylation of histone preparation III-S by wheat CDPK is not inhibited by flavonoids. The structural requirements for inhibition of wheat CDPK by flavonoids are more stringent than for inhibition of avian MLCK. Potent flavonoid inhibitors of wheat CDPK are unsaturated in 2,3 position, have hydroxyl groups in positions 3' and 4' and an additional hydroxyl in the chromone ring. Flavonoid glycosylation or methylation can abolish inhibition. A number of other naturally occurring plant phenolics including chalcones and gossypol also inhibit avian MLCK and wheat CDPK. Gossypol binds to calmodulin, abolishing Ca(2+)-dependent enhancement of dansyl-calmodulin fluorescence.

Animals↗
PubMed1991

Anti-inflammatory activity and inhibition of arachidonic acid metabolism by flavonoids.

A group of flavonoids isolated from medicinal plants and which are selective inhibitors of lipoxygenase activity in vitro: sideritoflavone, cirsiliol, hypolaetin-8-O-beta-D-glucoside, hypolaetin, oroxindin, quercetagetin-7-O-beta-D-glucoside, gossypin, hibifolin and gossypetin, besides leucocyanidol, have been studied for their effects on acute responses induced by carrageenin in mice. The oral administration of flavonoids to mice inhibited dose-dependently the development of paw oedema at 1, 3 and 5 h after carrageenin injection. A similar administration of flavonoids induced a dose-dependent inhibition of leukocyte accumulation in inflammatory exudates following intraperitoneal injection of carrageenin into mice. Some of the flavonoids exhibited a potency against leukocyte infiltration similar to that seen for inhibition of carrageenin oedema at 3 h of induction. In agreement with data reported in rats, indomethacin was much more effective on inhibition of prostaglandin E2 (PGE2) formation than on leukocyte infiltration in mice. The selectivity of flavonoids towards lipoxygenase is not retained in vivo since they behave as dual inhibitors of PGE2 and leukotriene B4 (LTB4) formation in peritoneal exudates. Our data support the inhibition of arachidonic acid metabolism as one of the mechanisms by which flavonoids exert their anti-inflammatory effects.

Animals↗