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Myricetin does not affect hemostasis in vivo. Myricetin at 25 mg/kg or 50 mg/kg as well as vehicle control were administered to healthy mice by oral gavage for three consecutive days. Tail bleeding was measured after tail tip amputation. Data expressed as mean ± SEM as well as individual points. There was no statistical difference between groups.
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Background
Flavonoids have been characterized as a prominent class of compounds to treat thrombotic diseases through the inhibition of thiol isomerases. Syzygium cumini is a flavonoid-rich medicinal plant that contains myricetin and gallic acid. Little is known about the potential antiplatelet properties of S. cumini and its constituent flavonoids....
Citations
... The molecular docking result showed that myricetin bound to the domain of PDI through non-covalent hydrogen bonds to inhibit its reductive activity. Myricetin also had an inhibitory effect on ERp5 [114]. ...
Vascular thiol isomerases (VTIs) encompass proteins such as protein disulfide isomerase (PDI), endoplasmic reticulum protein 5 (ERp5), ERp46, ERp57, ERp72, thioredoxin-related transmembrane protein 1 (TMX1), and TMX4, and play pivotal functions in platelet aggregation and formation of thrombosis. Investigating vascular thiol isomerases, their substrates implicated in thrombosis, the underlying regulatory mechanisms, and the development of inhibitors targeting these enzymes represents a rapidly advancing frontier within vascular biology. In this review, we summarize the structural characteristics and functional attributes of VTIs, describe the associations between these enzymes and thrombosis, and outline the progress in developing inhibitors of VTIs for potential antithrombotic therapeutic applications.
... Platelets were washed as described previously [19]. Blood was collected from healthy consenting volunteers, not using antiplatelet drugs, in tubes containing citrate buffer. ...
... An endoplasmic reticulum enzyme called protein disulfide isomerase (PDI) stimulates the creation of disulfide bonds in developing proteins, which in turn causes platelet aggregation and ensuing thrombosis [175]. MYR inhibits the function of PDI and its family member ERp5 reductase by creating non-covalent bonds between amino acids close to the protein's redox-active site [176]. ...
... Phosphate-buffered saline (PBS) with additions may keep polyphenols soluble. Adding non-ionic detergents like Triton X-100 or Tween 20 may reduce surface tension and avoid aggregation by inhibiting hydrophobic interactions [176]. Cyclodextrins and polyphenol inclusion complexes improve solubility and reduce aggregation. ...
Flavonoids are biologically active chemicals in various fruits, plants, vegetables, and leaves, which have promising uses in medicinal science. The health properties of these natural chemicals are widely accepted, and efforts are underway to extract the specific components referred to as flavonoids. Flavonoids demonstrate a diverse range of bio-activities, anticancer, antioxidant activity, anti-cholinesterase activity, antiinflammatory activity, antimalarial activity, antidiabetic activity, neurodegenerative disease, cardiovascular effect, hepatoprotective effects, and antiviral and antimicrobial activity. This study aims to examine the prevailing trends in flavonoid investigation studies, elucidate the activity of flavonoids, examine their various func-tions and uses, assess the potential of flavonoids as preventive medications for chronic diseases, and outline future research opportunities in this field. This review explores the diverse functions of flavonoids in preventing and managing various diseases.
... In mouse models, luteolin inhibited mesenteric artery thrombosis and collagen-adrenergic-induced pulmonary thrombosis without affecting coagulation, hemostasis, or platelet production [43]. The antiplatelet effect of aglycones may be mediated by inhibition of immunoreceptor tyrosine-based activation motif (ITAM), protein kinase B (PKB), phospholipase C (PLC), and mitogen-activated protein kinase (MAPK) [43,45]. ...
... Several studies have shown that flavonoid aglycones affect platelet activation via inhibition of ITAM, PKB, and PLC activity [43,45], which may be suppressed by activation of cyclic nucleotide-related signaling pathways [90]. However, the link between antiplatelet effects caused by aglycones and activation of these pathways has not been established before. ...
Flavonoid aglycones are secondary plant metabolites that exhibit a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, anticancer, and antiplatelet effects. However, the precise molecular mechanisms underlying their inhibitory effect on platelet activation remain poorly understood. In this study, we applied flow cytometry to analyze the effects of six flavonoid aglycones (luteolin, myricetin, quercetin, eriodictyol, kaempferol, and apigenin) on platelet activation, phosphatidylserine externalization, formation of reactive oxygen species, and intracellular esterase activity. We found that these compounds significantly inhibit thrombin-induced platelet activation and decrease formation of reactive oxygen species in activated platelets. The tested aglycones did not affect platelet viability, apoptosis induction, or procoagulant platelet formation. Notably, luteolin, myricetin, quercetin, and apigenin increased thrombin-induced thromboxane synthase activity, which was analyzed by a spectrofluorimetric method. Our results obtained from Western blot analysis and liquid chromatography–tandem mass spectrometry demonstrated that the antiplatelet properties of the studied phytochemicals are mediated by activation of cyclic nucleotide-dependent signaling pathways. Specifically, we established by using Förster resonance energy transfer that the molecular mechanisms are, at least partly, associated with the inhibition of phosphodiesterases 2 and/or 5. These findings underscore the therapeutic potential of flavonoid aglycones for clinical application as antiplatelet agents.
... These findings agree with those reported from the Egyptian flora (Sobeh et al., 2018a). Also, other Syzygium species showed similar chemical patterns, among them Syzygium cumini, Syzygium samarangense, Syzygium aqueum; they are polyphenolsrich medicinal plants containing myricetin and gallic acid (Sobeh et al., 2018b;Chagas et al., 2018;Sobeh et al., 2018c;Gaspar et al., 2020;Yassir et al., 2022). ...
The phytoconstituents of the aqueous extract from Syzygium jambos L. (Alston) leaves were defined using HPLC-PDA-MS/MS and the antioxidant, anti-aging, antibacterial, and anti-biofilm activities of the extract were in silico and in vitro investigated. The antioxidant activities were performed using in vitro DPPH and FRAP assays as well as H2-DCFDA assay in HaCaT cells in which oxidative stress was induced by UVA radiation. Anti-aging activity was tested in vitro, using aging-related enzymes. The antibacterial, anti-biofilm and inhibitory effects on bacterial mobilities (swarming and swimming) were assessed against Pseudomonas aeruginosa. Results showed that S. jambos aqueous extract contained 28 phytochemicals belonging to different metabolite classes, mainly phenolic acids, gallic acid derivatives, flavonoids, and ellagitannins. Mineral content analysis showed that S. jambos leaves contained moderate amounts of nitrogen, potassium, manganese, magnesium, and zinc, relatively low amounts of phosphorus and copper, and high concentration of calcium and iron. The extract displayed strong antioxidant activities in vitro and inhibited UVA-induced oxidative stress in HaCaT cells. Docking the major compounds identified in the extract into the four main protein targets involved in skin aging revealed an appreciable inhibitory potential of these compounds against tyrosinase, elastase, hyaluronidase, and collagenase enzymes. Moreover, molecular dynamic simulations were adopted to confirm the binding affinity of some selected compounds towards the target enzymes. The extract exhibited pronounced in vitro anti-aging effects, compared to kojic acid and quercetin (the reference compounds). It also inhibited the growth of P. aeruginosa, counteracted its ability to form biofilm, and impeded its swarming and swimming mobilities. Altogether, these findings strongly propose S. jambos leaves as a promising source of bioactive metabolites for the development of natural cosmeceutical and dermatological agents.
... These findings agree with those reported from the Egyptian flora (Sobeh et al., 2018a). Also, other Syzygium species showed similar chemical patterns, among them Syzygium cumini, Syzygium samarangense, Syzygium aqueum; they are polyphenolsrich medicinal plants containing myricetin and gallic acid (Sobeh et al., 2018b;Chagas et al., 2018;Sobeh et al., 2018c;Gaspar et al., 2020;Yassir et al., 2022). ...
The phytoconstituents of the aqueous extract from Syzygium jambos L. (Alston) leaves were defined using HPLC-PDA-MS/MS and the antioxidant, anti-aging, antibacterial, and antibiofilm activities of the extract were in silico and in vitro investigated. The antioxidant activities were performed using in vitro DPPH and FRAP assays as well as H2-DCFDA assay in HaCaT cells in which oxidative stress was induced by UVA radiation. Anti-aging activity was tested in vitro, using aging-related enzymes. The antibacterial, anti-biofilm and inhibitory effects on bacterial mobilities (swarming and swimming) were assessed against P. aeruginosa. Results showed that S. jambos aqueous extract contained 28 phytochemicals belonging to different metabolite classes, mainly phenolic acids, gallic acid derivatives, flavonoids, and ellagitannins.Mineral content analysis showed that S. jambos leaves contained moderate amounts of nitrogen, potassium, manganese, magnesium, and zinc, relatively low amounts of phosphorus and copper, and high concentration of calcium and iron. The extract displayed strong antioxidant activities in vitro and inhibited UVA-induced oxidative stress in HaCaT cells. Docking the major compounds identified in the extract into the four main protein targets involved in skin aging revealed an appreciable inhibitory potential of these compounds against tyrosinase, elastase, hyaluronidase, and collagenase enzymes. Moreover, molecular dynamic simulations were adopted to confirm the binding affinity of some selected compounds towards the target enzymes. The extract exhibited pronounced in vitro anti-aging effects, compared to kojic acid and quercetin (the reference compounds). It also inhibited the growth of P. aeruginosa, counteracted its ability to form biofilm, and impeded its swarming and swimming mobilities. Altogether, these findings strongly propose S. jambos leaves as a promising source of bioactive metabolites for the development of natural cosmeceutical and dermatological agents.
... Moreover, MYR has proved effective in inhibiting ERp5 and protein disulfide isomerase (PDI), therefore showing potential as a novel therapeutic agent for thrombotic disorders. Gaspar et al., 2020 MYR lowers BV2 microglial neuroinflammation via inhibition of the MAPK signaling pathway and the production of proinflammatory modulators and cytokines. Hence, MYR could be useful as a treatment for neuroinflammatory diseases. ...
... Therefore, myricetin has been claimed to display anti-platelet effect by reducing the spreading frequency of platelets on collagen associated with the thrombi formation. This finding has unveiled an alternative therapeutic source to manage thrombotic disorders (Gaspar et al. 2019). ...
Myricetin is a yellow crystal of dietary flavonoid which is commonly found in plants from Anacardiaceae, Myricaceae, Pinaceae, Polygonaceae, and Primulaceae families. The myricetin glycosides are predominantly present in different categories of plant-based foods and beverages, including the fruits, vegetables, herbs, legumes, tea, wines, bee pollen, and honey. Many clinical trials, in vivo, and in vitro investigations have suggested that myricetin contributes to its variability in health benefit effects, including anticancer, anti-hypertensive, anti-inflammatory, anti-diabetic, anti-neurotoxicity, anti-ageing, cardioprotective, and immunomodulatory activities. Due to its high commercial values, myricetin is a biomolecule favoured for mass production. The production of myricetin derivatives with optimal oral bioavailability shall offer greater therapeutic effect. This chapter shall cover all the current finding about myricetin, encompassing its main resources, physicochemical properties, biosynthesis, metabolism, and pharmacological activities with discussion emphasis on its mechanism of action, toxicity, and safety. The highlight on several product patents related to myricetin shall shed more insight for its cosmeceutical and nutraceutical values.
... Our study reveals the direct correlation of PDI and NOX in platelets starting from the complexity of cell proteins through to the analysis of how each protein impacts platelet function. The data follow several experimental reports from our labs [34,[59][60][61]. We conclude that the five enzymes analyzed in platelets regulate more than 200 proteins, which in turn can interact with more than the other 2600 proteins involved in relevant biological Figure 10. ...
... Our study reveals the direct correlation of PDI and NOX in platelets starting from the complexity of cell proteins through to the analysis of how each protein impacts platelet function. The data follow several experimental reports from our labs [34,[59][60][61]. We conclude that the five enzymes analyzed in platelets regulate more than 200 proteins, which in turn can interact with more than the other 2600 proteins involved in relevant biological processes. ...
Oxidative stress participates at the baseline of different non-communicable pathologies such as cardiovascular diseases. Excessive formation of reactive oxygen species (ROS), above the signaling levels necessary for the correct function of organelles and cells, may contribute to the non-desired effects of oxidative stress. Platelets play a relevant role in arterial thrombosis, by aggregation triggered by different agonists, where excessive ROS formation induces mitochondrial dysfunction and stimulate platelet activation and aggregation. Platelet is both a source and a target of ROS, thus we aim to analyze both the platelet enzymes responsible for ROS generation and their involvement in intracellular signal transduction pathways. Among the proteins involved in these processes are Protein Disulphide Isomerase (PDI) and NADPH oxidase (NOX) isoforms. By using bioinformatic tools and information from available databases, a complete bioinformatic analysis of the role and interactions of PDI and NOX in platelets, as well as the signal transduction pathways involved in their effects was performed. We focused the study on analyzing whether these proteins collaborate to control platelet function. The data presented in the current manuscript support the role that PDI and NOX play on activation pathways necessary for platelet activation and aggregation, as well as on the platelet signaling imbalance produced by ROS production. Our data could be used to design specific enzyme inhibitors or a dual inhibition for these enzymes with an antiplatelet effect to design promising treatments for diseases involving platelet dysfunction.
... Janssen et al. [19] found that 2500 mmol/l of flavonol quercetin significantly inhibited collagen and ADP-induced platelet aggregation in platelet-rich plasma and washed platelets by approximately 80-97%. Flavonoids have been shown to have a number of antithrombotic actions [20,21] Both in vitro incubation and oral supplementation with select flavonoid fractions isolated from purple grape juice (PGJ) decrease platelet aggregation, increase platelet-derived NO release, and decrease superoxide production [22]. Due to their anti-platelet activity, the consumption of bioactives derived from plant foods, particularly flavonoids, has shown antithrombotic and cardiovascular protective effects [5,23]. ...
Objective: In this study, we aimed to isolate a polyphenolic compound from a polyphenolic-rich fraction from Emblica officinalis fruits and also study its effect on adenosine diphosphate (ADP) and collagen-induced in vitro platelet aggregation. Methods: The polyphenolic-rich fraction was prepared by 80% methanolic extraction. The residue was extracted successively with hexane, benzene, ethyl acetate and n-butanol. Ethyl acetate residue was selected for column chromatography because of its high polyphenolic content. It was subjected to repeated column chromatography of series with different eluents of increasing polarity. A brown amorphous powder was obtained from ethyl acetate: methanol (7:3) fraction. This sample was subjected to UV-visible spectrum, IR spectrum, 1 H NMR, 13 C NMR and electrospray mass spectrum (ES-MS) studies for its structural elucidation. Results: A compound, 5, 7, 4'-trihydroxy 3'-methoxy isoflavanone was identified from polyphenolic rich ethyl acetate: methanol (7:3) fraction separated from the 80% methanolic extract of Embica officinalis fruits by repeated column chromatography. Yield of the compound was 421.05 mg/kg. This compound exhibited antiplatelet activity well comparable with that of quercetin. Conclusion: The present study proved that the isolated compound 5, 7, 4'-trihydroxy 3'-methoxy isoflavanone exerts a significant inhibitory activity on ADP and collagen-induced in vitro platelet aggregation, which can be considered as an effective remedy for alleviating complications of cardiovascular diseases.
