INTRODUCTION: It is well known that platelets from diabetic patients can be resistant to clinically used antiplatelet drugs. METHODS: To assess the phenomenon in more detail, 50 adult patients suffering from type 1 diabetes mellitus (T1D) were recruited and their responses to 7 platelet aggregation inducers, as well as to 3 clinically used antiplatelet drugs (acetylsalicylic acid /ASA/, ticagrelor and vorapaxar) and one experimental compound, 4-methylcatechol, were assessed ex vivo. A control group of 50 generally healthy age-matched controls was also included for comparison. RESULTS: T1D patients exhibited a lower aggregation reaction to 3 inducers but were conversely more resistant to the effect of ASA and vorapaxar than controls. Ticagrelor tended to be less active in T1D as well. On the other hand, 4-methylcatechol was equally or even more potent in T1D than in healthy controls. Plasma glucose levels above 7 mM were associated with lower platelet aggregation responses to four aggregation inducers. In contrast, the effect of 4-methylcatechol, unlike that of ASA, did not appear to be strongly influenced by glycemia. Further subanalyses, excluding hypertensive patients and significantly more frequently administered drugs, did not substantially modify the results. CONCLUSION: Conclusively, 4-methylcatechol seems to be a prototypical antiplatelet compound with a strong effect even in diabetic patients.

• Keywords
• 4-methylcatechol, Aggregation, Diabetes mellitus, Platelets,
• MeSH
• Platelet Aggregation * drug effects   MeSH
• Aspirin * therapeutic use   pharmacology   adverse effects   MeSH
• Diabetes Mellitus, Type 1 * blood   diagnosis   drug therapy   MeSH
• Adult MeSH
• Platelet Aggregation Inhibitors * therapeutic use   adverse effects   pharmacology   MeSH
• Catechols * therapeutic use   pharmacology   MeSH
• Blood Glucose metabolism   drug effects   MeSH
• Lactones * therapeutic use   pharmacology   MeSH
• Drug Resistance MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Pyridines * therapeutic use   pharmacology   MeSH
• Case-Control Studies MeSH
• Ticagrelor therapeutic use   MeSH
• Blood Platelets * drug effects   metabolism   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• Aspirin * MeSH
• Platelet Aggregation Inhibitors * MeSH
• Catechols * MeSH
• Blood Glucose MeSH
• Lactones * MeSH
• Pyridines * MeSH
• Ticagrelor MeSH
• vorapaxar MeSH Browser

The human body is regularly exposed to simple catechols and small phenols originating from our diet or as a consequence of exposure to various industrial products. Several biological properties have been associated with these compounds such as antioxidant, anti-inflammatory, or antiplatelet activity. Less explored is their potential impact on the endocrine system, in particular through interaction with the alpha isoform of the estrogen receptor (ERα). In this study, human breast cancer cell line MCF-7/S0.5 was employed to investigate the effects on ERα of 22 closely chemically related compounds (15 catechols and 7 phenols and their methoxy derivatives), to which humans are widely exposed. ERα targets genes ESR1 (ERα) and TFF1, both on mRNA and protein level, were chosen to study the effect of the tested compounds on the mentioned receptor. A total of 7 compounds seemed to impact mRNA and protein expression similarly to estradiol (E2). The direct interaction of the most active compounds with the ERα ligand binding domain (LBD) was further tested in cell-free experiments using the recombinant form of the LBD, and 4-chloropyrocatechol was shown to behave like E2 with about 1/3 of the potency of E2. Our results provide evidence that some of these compounds can be considered potential endocrine disruptors interacting with ERα.

• Keywords
• catechol, cytotoxicity, endocrine disruptor, estrogenicity, xenobiotic,
• MeSH
• Estrogen Receptor alpha * metabolism   genetics   MeSH
• Endocrine Disruptors * pharmacology   toxicity   MeSH
• Trefoil Factor-1 metabolism   genetics   MeSH
• Phenols * pharmacology   chemistry   MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Breast Neoplasms metabolism   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Estrogen Receptor alpha * MeSH
• Endocrine Disruptors * MeSH
• ESR1 protein, human MeSH Browser
• Trefoil Factor-1 MeSH
• Phenols * MeSH
• TFF1 protein, human MeSH Browser

A polyphenol-rich diet has beneficial effects on cardiovascular health. However, dietary polyphenols generally have low bioavailability and reach low plasma concentrations. Small phenolic metabolites of these compounds formed by human microbiota are much more easily absorbable and could be responsible for this effect. One of these metabolites, 4-methylcatechol (4-MC), was suggested to be a potent anti-platelet compound. The effect of 4-MC was tested ex vivo in a group of 53 generally healthy donors using impedance blood aggregometry. The mechanism of action of this compound was also investigated by employing various aggregation inducers/inhibitors and a combination of aggregometry and enzyme linked immunosorbent assay (ELISA) methods. 4-MC was confirmed to be more potent than acetylsalicylic acid on both arachidonic acid and collagen-triggered platelet aggregation. Its clinically relevant effect was found even at a concentration of 10 μM. Mechanistic studies showed that 4-MC is able to block platelet aggregation caused by the stimulation of different pathways (receptors for the von Willebrand factor and platelet-activating factor, glycoprotein IIb/IIIa, protein kinase C, intracellular calcium elevation). The major mechanism was defined as interference with cyclooxygenase-thromboxane synthase coupling. This study confirmed the strong antiplatelet potential of 4-MC in a group of healthy donors and defined its mechanism of action.

• Keywords
• aggregation, blood, flavonoid, human, metabolite, platelet,
• MeSH
• Phenols MeSH
• Immunologic Tests * MeSH
• Catechols * pharmacology   MeSH
• Humans MeSH
• Polyphenols MeSH
• Platelet Function Tests MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 4-methylcatechol MeSH Browser
• Phenols MeSH
• Catechols * MeSH
• Polyphenols MeSH