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

Familial hypercholesterolemia (FH) is a relatively rare genetic disease associated with high serum cholesterol levels but also with abnormalities in blood coagulation. Novel pharmacotherapeutic approaches in FH including proprotein convertase subtilisin/kexin type 9 antibodies (PCSK9Ab) are very efficient in decreasing cholesterol levels but their impact on coagulation in FH is not yet established. Therefore, we hypothesized that these novel antidyslipidemic drugs can positively impact blood coagulation due to their more potent effect on cholesterol. A total of 15 healthy volunteers and all 15 available patients with severe FH treated at the University Hospital Hradec Králové were enrolled, coagulation was assessed by mechanic coagulometer, and the impact of four clinically used direct anticoagulants was analyzed ex vivo. FH patients were treated effectively as their total cholesterol was 4.11 ± 1.57 mM and LDL cholesterol was 2.44 ± 1.46 mM, which were even lower values than detected in our generally healthy controls. Twelve from the 15 FH patients were finally analyzed as 3 were treated with anticoagulants. Coagulation in FH patients was prolonged more extensively by dabigatran and rivaroxaban, when compared to healthy controls. Treatment with PCSK9Ab or lipid apheresis did not seem to have a significant effect on coagulation. The latter procedure however significantly decreased serum levels of one vitamin K form, MK4. Shorter coagulation time was associated with higher levels of LDL, non-HDL, and total cholesterol. Current treatment of FH seems to improve the effects of direct anticoagulants beyond known effects on LDL cholesterol levels.

• Keywords
• Direct anticoagulants, Familial hypercholesterolemia, Proprotein convertase subtilisin/kexin type 9, Vitamin K,
• MeSH
• Anticholesteremic Agents therapeutic use   MeSH
• Anticoagulants * therapeutic use   pharmacology   MeSH
• Cholesterol blood   MeSH
• Dabigatran therapeutic use   pharmacology   MeSH
• Adult MeSH
• Blood Coagulation * drug effects   MeSH
• Hyperlipoproteinemia Type II * blood   drug therapy   MeSH
• Hypolipidemic Agents * therapeutic use   pharmacology   MeSH
• Cholesterol, LDL blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• PCSK9 Inhibitors MeSH
• Rivaroxaban therapeutic use   pharmacology   MeSH
• Case-Control Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anticholesteremic Agents MeSH
• Anticoagulants * MeSH
• Cholesterol MeSH
• Dabigatran MeSH
• Hypolipidemic Agents * MeSH
• Cholesterol, LDL MeSH
• PCSK9 Inhibitors MeSH
• PCSK9 protein, human MeSH Browser
• Proprotein Convertase 9 MeSH
• Rivaroxaban MeSH

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