P2Y Receptors Research Articles

Temporary and reversible clopidogrel, ticagrelor and prasugrel high on-treatment platelet reactivity associated to the concomitant use of morphine and fentanyl in acute coronary syndrome

Background: Recent evidence demonstrates that morphine significantly reduces absorption and delays onset of action of P2Y12-receptor inhibitors in patients with acute coronary syndrome. Case summary: 55-year-old male with inferior ST-segment–elevation myocardial infarction was treated with opioids previous and during primary angioplasty, developing temporary and reversible clopidogrel, ticagrelor and prasugrel high on-treatment platelet reactivity assessed by platelet function test. We treated with glycoprotein IIb/IIIa inhibitor as a bridge to obtain antplatelet effect by P2Y12–receptor inhibitors. Discussion: The interaction between opioids and oral P2Y12-receptor inhibitors in patients with acute coronary syndrome should be highlighted. Although morphine administration may potentially lead to detrimental clinical consequences by diminish of antiplatelet effect, its routine avoidance cannot be recommended until large scale trials be available. We suggest that if the use of morphine and other opioids is inevitable, utilization of platelet function tests to guide the antiplatelet treatment is an option.

New insights into geraniol's antihemolytic, anti-inflammatory, antioxidant, and anticoagulant potentials using a combined biological and in silico screening strategy.

The study aims to assess the antihemolytic and antioxidant activities of geraniol versus 2, 2'-azobis, 2-amidinopropane dihydro-chloride- (AAPH-) induced oxidative damage and hemolysis to erythrocytes and its anti-inflammatory potential against lipopolysaccharide- (LPS-) induced inflammation in white blood cells (WBCs) with a focus on its integrated computational strategies against different targeted receptors participating in inflammation and coagulation. The rats' erythrocyte suspension was incubated with different geraniol concentrations. Molecular docking and simulation were used to explore the possible interaction patterns of geraniol against the potential targeted proteins for therapeutic screening. The results displayed that geraniol had a prolonged noteworthy effect on activated partial thromboplastin time and thromboplastin time. Geraniol displayed strong antioxidant effects via reduced malondialdehyde (MDA) formation and increased GSH level and SOD activity. We observed dose-dependent prevention of K+ ion leakage along with a remarkable decline of hemolysis in erythrocytes pretreated with geraniol. Geraniol 100µg/mL and diclofenac 100µM were nontoxic to WBCs. Geraniol significantly reduces the expression and release of cellular pro-inflammatory factors TNF-α, IL-1β, IL-8, and nitric oxide, accompanied by a significant upregulation of gene expression of anti-inflammatory cytokine IL-10 in LPS-induced WBCs compared to nontreated cells. It demonstrates a much stronger inhibition potential than diclofenac in terms of inflammation inhibition. When comparing molecular docking and simulation data, current work showed that geraniol has a good affinity toward apoptosis signal-regulating kinase 1 (ASK1) and human P2Y12 receptors and could be developed as an antioxidant, anti-inflammatory, and anticoagulant medication in the future. Consequently, geraniol is recommended to have a defensive influence against oxidative stress, and hemolysis also could be developed as a promising anti-inflammatory, antioxidant, and anticoagulant medication.

Ionotropic P2X4 and P2X7 receptors in the regulation of ion transport across rat colon.

ATP plays an important role as an extracellular messenger acting via different types of purinoceptors. Whereas most of the actions of ATP at intestinal epithelia are thought to be mediated by metabotropic P2Y receptors, the role of ionotropic P2X receptors remains unclear. Consequently, we investigated the role of P2X4 and P2X7 receptors on ion transport across rat colonic epithelia by using BzATP, a potent agonist at P2X7 (and weak agonist at P2X4). Ussing chamber and Ca2+ imaging experiments were performed on rat colonic epithelia, combined with P2X receptor expression studies. Ussing chamber experiments revealed that serosal BzATP induced a neuronally mediated increase in short-circuit current caused by Cl- secretion. In contrast, the effect of mucosal BzATP was smaller, insensitive to tetrodotoxin and Cl- -independent. When epithelia were basolaterally depolarized to measure currents across the apical membrane, BzATP stimulated a cation current consistent with the activation of apical nonselective cation channels. Experiments with isolated colonic crypts revealed a BzATP-induced increase in the cytosolic Ca2+ concentration. Sensitivity to antagonists indicates stimulation of P2X4 and P2X7 receptors by serosal BzATP and of P2X7 receptors by mucosal BzATP. A similar pattern was observed with native ATP, which induced larger transepithelial currents in comparison to BzATP. RT-PCR and immunohistochemistry experiments confirmed the expression of P2X4 and P2X7 receptors in the colon localized in the epithelium and in submucosal ganglia. Epithelial and neuronal ionotropic P2X receptors are involved in the regulation of intestinal ion transport.

Things We Do for No Reason™: Routine pretreatment with a P2Y12 receptor inhibitor before invasive coronary angiography for patients with a non-ST elevation acute coronary syndrome.

The authors declare no conflict of interest.

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease.

SummaryDysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

Pleiotropic Effects of Ticagrelor: Influence on CYP4F2 Gene and Protein Expression in HUVEC and HepG2, and Escherichia coli Bacterial Survival.

BackgroundAntiplatelet drugs, such as ticagrelor, which target platelet P2Y12 receptors, are used for prevention of ischemic heart disease. Ticagrelor is also known to have pleiotropic effects of unknown mechanisms. Ticagrelor could influence the expression of molecules involved in resolution of inflammation. This study aimed to investigate if ticagrelor could change the expression of CYP4F2 and its encoded protein concentration and, additionally, to determine ticagrelor possible antibacterial activity against gram-negative bacteria.MethodsCYP4F2 expression was determined in HUVEC and HepG2 cell lines by qPCR. CYP4F2 protein concentration was determined by ELISA. Antibiotic susceptibility testing was performed using a disc diffusion method.ResultsTicagrelor was observed to reduce the expression of CYP4F2 in HUVEC and HepG2 cell lines. It also reduced CYP4F2 protein levels in HUVEC cells. Ticagrelor had no bactericidal activity against gram-negative third generation cephalosporin resistant E. coli.ConclusionTicagrelor reduced CYP4F2 protein concentration in HUVEC, and CYP4F2 expression in HUVEC and HepG2 cells, but had no effect on third-generation cephalosporin-resistant E. coli strains.

Molecular mechanisms modulating hemostasis and development of acute pyelonephritis after contact ureteral lithotripsy

BACKGROUND: Improving the efficiency and reducing the frequency of complications of surgical treatment of urolithiasis is an actual problem in urology.
 AIM: To establish the molecular mechanisms that modulate the hemostasis and development of acute pyelonephritis after percutaneous contact ureteral lithotripsy.
 MATERIALS AND METHODS: The study included 21 patients with urolithiasis and concretions in the upper third of the ureter in whom, after standard lithokinetic therapy for 7 days, according to imaging control data, the calculus did not move from the pyelo-ureteral zone to the middle third of the ureter. All patients underwent contact ureteral lithotripsy. After the operation, nonsteroidal anti-inflammatory drugs and antibiotics were used for 2 days. The severity of hematuria and leukocyturia was assessed 24, 48, and 72 h after contact ureteral lithotripsy. Functional activity receptors were analyzed in vitro on a platelet suspension. Platelet aggregation was assessed by the turbidimetric method using a ChronoLog analyzer (USA).
 RESULTS: At 24, 48, and 72 h after contact ureteral lithotripsy, a significant decrease was found in the severity of microhematuria (p 0.001). The leukocyturia level decreased over 48 h (p 0.05) and increased 72 h after surgery (p 0.001). The above dynamics of complications after hours indicates that two pathological processes simultaneously develop in the ureteral mucosa: induction of thrombogenesis and modulation of an acute inflammatory reaction. Аfter 24 h of NSAID discontinuation (3 days after contact ureteral lithotripsy), normoreactivity of the 2-adrenergic receptors, GPVI receptors, AT1 receptors, PAF receptors, P2X1 receptors, and A2A receptors was found, as well as hyporeactivity of purine P2Y receptors and 2-adrenergic receptors. The correlation between the severity of hematuria and the activity of GPVI receptors for collagen, 2-adrenergic receptors for adrenaline, and AT1 receptors for angiotensin-2 (p 0.05) makes it possible to specify the possible interaction of platelet receptors that maintain hemostasis during inhibition of the COXTxA2 axis. Maintaining the severity of pyelonephritis after contact ureteral lithotripsy is associated with the interaction of the PAF receptors, purine ionotropic P2X1 receptors, and 2-adrenergic receptors on blood cells.
 CONCLUSIONS: The analysis of targets receptors on platelets and leukocytes after contact ureteral lithotripsy in the upper third of the ureter with ineffective lithokinetic therapyallows us to outline ways to improve conservative therapy to limit the development of postoperative complications.

Aβ1-42 peptides blunt the adenosine A2A receptor-mediated control of the interplay between P2X7 and P2Y1 receptors mediated calcium responses in astrocytes.

The contribution of astrocytes to Alzheimer's disease (AD) is still ill defined. AD involves an abnormal accumulation of amyloid-β peptides (Aβ) and increased production of danger signals such as ATP. ATP can direct or indirectly, through its metabolism into adenosine, trigger adaptive astrocytic responses resulting from intracellular Ca2+ oscillations. AD also triggers an upregulation of astrocytic adenosine A2A receptors (A2AR), which blockade prevents memory dysfunction in AD. We now investigated how Aβ peptides affect ATP-mediated Ca2+ responses in astrocytes measured by fluorescence live-cell imaging and whether A2AR control astrocytic Ca2+ responses mediated by ATP receptors, mainly P2X7R and P2Y1R. In primary cultures of rat astrocytes exposed to Aβ1-42, ATP-evoked Ca2+ responses had a lower amplitude but a longer duration than in control astrocytes and involved P2X7R and P2Y1R, the former potentiating the later. Moreover, Aβ1-42 exposure increased protein levels of P2Y1R in astrocytes. A2AR antagonism with SCH58261 controlled in a protein kinase A-dependent manner both P2X7R- and P2Y1R-mediated Ca2+ responses in astrocytes. The interplay between these purinoceptors in astrocytes was blunted upon exposure to Aβ1-42. These findings uncover the ability of A2AR to regulate the inter-twinned P2X7R- and P2Y1R-mediated Ca2+ dynamics in astrocytes, which is disrupted in conditions of early AD.

Ideal P2Y12 Inhibitor in Acute Coronary Syndrome: A Review and Current Status.

Dual antiplatelet therapy (DAPT) has remained the cornerstone for management of acute coronary syndrome (ACS) over the years. Clopidogrel has been the quintessential P2Y12 receptor (platelet receptor for Adenosine 5′ diphosphate) inhibitor for the past two decades. With the demonstration of unequivocal superior efficacy of prasugrel/ticagrelor over clopidogrel, guidelines now recommend these agents in priority over clopidogrel in current management of ACS. Cangrelor has revived the interest in injectable antiplatelet therapy too. Albeit the increased efficacy of these newer agents comes at the cost of increased bleeding and this becomes more of a concern when combined with aspirin. Which P2Y12i is superior over another has been intensely debated over last few years after the ISAR-REACT 5 study with inconclusive data. Three novel antiplatelet agents are already in the pipeline for ACS with all of them succeeding in phase II studies. The search for an ideal antiplatelet remains a need of the hour for optimal reduction of ischemic events in ACS.

Adherence of ticagrelOr in real world patients with aCute coronary syndrome: The AD-HOC study.

BackgroundDual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor antagonist is the cornerstone of therapy in patients with acute coronary syndrome (ACS). Adherence to medical therapy is an important issue, as premature DAPT discontinuation increases the risk of new ischemic events. The aim of the present observational prospective multicenter study was to evaluate in the real-world incidence and discontinuation patterns of ticagrelor during the first 12 months after ACS.MethodsWe analyzed 431 ACS patients, discharged with ticagrelor, by 7 Italian centers. The primary end-point was the incidence of cessation of ticagrelor up to 12 months from the index event.ResultsDefinitive ticagrelor cessations occurred in 52 patients (12.1%), of which 35 were discontinuations (clinically driven) and 17 disruptions (due to acute events). Temporary cessation occurred in 14 cases (3.3%). Age ≥ 80 years and anticoagulant therapy were independent predictors of premature discontinuation. Bleeding occurred in 74 patients, of which 25 suffered a BARC ≥ 2 bleeding event. Bleeding were more frequent in female sex (27.0% vs 17.2%, p-value 0.049) and in patients with a history of bleeding (8.1% vs 2.9%, p-value 0.035).ConclusionsOur study found that the adherence to DAPT with ticagrelor after an ACS is still an important issue, premature discontinuation occurred mainly in fragile patients, like elderly, who suffered a previous bleeding or underwent previous percutaneous coronary intervention.

The blockage of downstream P2Y2 receptor signaling inhibits the prostate cancer cell adhesion to endothelial cells

AimsProstate cancer is the second most frequently malignancy in men worldwide. Most deaths are caused by metastasis, and tumor cell dissemination involves the interaction with endothelial cells. However, the endothelial cell signaling involved in such interaction is not entirely understood. The tumor microenvironment contains extracellular ATP, an endogenous agonist of the purinergic P2Y2 receptor (P2Y2R). P2Y2R signaling changes endothelial cell phenotype, which may be relevant to cancer pathophysiology. Therefore, we hypothesized that P2Y2R activation could favor the metastatic prostate cancer cells adhesion to endothelial cells. Main methodsFor adhesion assays, confluent endothelial cells EA.hy926 were treated with P2Y2R agonists before adding and imaging stained DU-145 cells. Alternatively, fluorescent probes and antibodies were used to determine intracellular endothelial Ca2+, nitric oxide (NO), and flow cytometry assays. Key findingsEndothelial P2Y2R activation with ATP, UTP, or the selective agonist 2-thio-UTP increased DU-145 cell adhesion to EA.hy926 cells. This effect required endothelial cell Ca2+ mobilization and relied on the endothelial expression of VCAM-1 and ICAM-1. Conversely, inhibiting this proadhesive endothelial phenotype could impair DU-145 cell adhesion. To evaluate this, we chose atorvastatin based on its notable improvement of endothelial cell dysfunction. Atorvastatin blocked UTP-induced DU-145 cell adhesion to endothelial cell monolayer in a NO-dependent manner, unveiling a P2Y2R and NO signaling crosstalk. SignificanceEndothelial P2Y2R signaling contributes to the adhesion of metastatic prostate cancer cells suggesting that the downstream signaling blockade by statins could be a putative mechanism to reduce prostate cancer metastasis.

The Cost of Breaking Even: a Perspective on the Net Clinical Impact of Adding Aspirin to Antithrombotic Therapies in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

Outcomes from randomized controlled trials (RCTs) inform the latest recommendations on percutaneous coronary intervention (PCI) management of a short period of oral anticoagulation (OAC), a P2Y12 receptor inhibitor, and aspirin for 1week or until hospital discharge in patients with atrial fibrillation (AF) undergoing PCI, and up to 4weeks in individuals considered to be at high-risk for ischemic events, followed by discontinuation of aspirin and continuation of OAC and a P2Y12 inhibitor for up to 12months. We examined and summarized the outcomes of bleeding and major adverse cardiac events (MACEs) from RCTs and meta-analyses, published between 2013 and 2022, comparing therapy with OAC and a P2Y12 inhibitor with and without aspirin in AF patients undergoing PCI with stenting. Data comparing dual therapy with OAC and a P2Y12 inhibitor alone to triple therapy with OAC, a P2Y12 inhibitor, and aspirin with respect to the risks of MACEs, including stent thrombosis within the first 30days, are underpowered and inconclusive. The addition of aspirin does not appear to be associated with a decreased risk of ischemic events, even in patients with high-risk CHA2DS2-VASc scores, but does significantly increase bleeding hazards. The increased safety of newer generation drug-eluting stents may have further minimized any theoretical anti-ischemic benefits of aspirin. The possible attenuation of the pleiotropic effects of concomitant cardiovascular medications by aspirin may also have been a contributing factor. The addition of aspirin to OAC and a P2Y12 inhibitor is likely associated with a net clinical harm in patients with AF who undergo PCI with stenting, even within the first 1-4weeks after PCI. Revisiting the guideline recommendations to administer aspirin in this timeframe may be warranted.

Potential antiplatelet aggregation metabolites from the discarded sorghum (Sorghum bicolor L.) root

Sorghum (Sorghum bicolor L.) is the fifth largest crop in the world and has potential health benefits, but vast quantities of sorghum roots are discarded after harvest. Based on the previous antiplatelet aggregation for this species, two new multi-substituted 3H-indole alkaloids sorghumine A (1) and sorghumine B (2), together with 14 known compounds (3–16), were found from the water extract of sorghum roots. Compounds 1–2 were identified by analyzing their spectroscopic data and physic and chemical properties, and the absolute configuration was further determined by electronic circular dichroism (ECD) analysis and calculations. 1–2, 4, 6–8 and 13–15 showed significant inhibition of platelet aggregation induced by adenosine diphosphate. 2–4, 6–9 and 11 showed significant inhibition of platelet aggregation induced by collagen. 4–6, 8, 10–11 and 16 showed significant inhibition on platelet aggregation induced by thrombin. Furthermore, molecular docking showed that active compounds can bind to P2Y12 and COX-1 receptors in platelet.

P2Y12 inhibitor pretreatment in patients with nonST-segment elevation acute coronary syndrome: A meta-analysis.

Background:The 2020 European Society of Cardiology guidelines do not recommend pretreatment for nonST-segment elevation myocardial infarction (NSTEMI) patients with unclear coronary anatomy, which is inconsistent with our routine preoperative approach to loading P2Y12 receptor inhibitors (e.g., preoperative loading of 300 mg of clopidogrel).Objectives:The purpose of our study was to compare the safety and effectiveness of P2Y12 inhibitors administered before coronary angiography or at least before percutaneous coronary intervention (PCI) with during or after PCI.Methods:Cochrane, PubMed, and Embase databases were searched. The primary effect endpoint and safety endpoint were any-cause death and major bleeding, respectively. Major adverse cardiovascular events, myocardial infarction and revascularization were also analyzed.Results:Our search identified 9 trials. P2Y12 inhibitor pretreatment was associated with lower death from any cause (OR 0.62, 95% CI 0.53–0.72, P < 0.00001) without increasing the risk of bleeding (OR 1.02, 95% CI 0.80–1.30, P = 0.89). However, prasugrel or ticagrelor pretreatment was not associated with a lower risk of mortality (OR 0.70, 95% CI 0.31–1.59, P = 0.40) and increased the risk of bleeding (OR 1.67, 95% CI 1.10–2.54, P = 0.02).Conclusions:In summary, clopidogrel pretreatment was associated with significantly lower mortality, major adverse cardiovascular events, myocardial infarction and revascularization with no increase in major bleeding. However, these advantages were not observed with prasugrel or ticagrelor pretreatment.

Brain Damage-linked ATP Promotes P2X7 Receptors Mediated Pineal N-acetylserotonin Release

The pineal gland is a key player in surveillance and defense responses. In healthy conditions, nocturnal circulating melatonin (MEL) impairs the rolling and adhesion of leukocytes to the endothelial layer. Fungi, bacteria, and pro-inflammatory cytokines block nocturnal pineal MEL synthesis, facilitating leukocyte migration to injured areas. ATP is a cotransmitter of the noradrenergic signal and potentiates noradrenaline (NAd)-induced MEL synthesis via P2Y1 receptor (P2Y1R) activation. Otherwise, ATP low-affinity P2X7 receptor (P2X7R) activation impairs N-acetylserotonin (NAS) into MEL conversion in NAd incubated pineals. Here we mimicked a focal increase of ATP by injecting low (0.3 and 1.0 µg) and high (3.0 µg) ATP in the right lateral ventricle of adult rats. Nocturnal pineal activity mimicked the in culture data. Low ATP doses increased MEL output, while high ATP dose and the P2X7R agonist BzATP (15.0–50.0 ng) increased NAS pineal and blood content. In the brain, the response was structure-dependent. There was an increase in cortical and no change in cerebellar MEL. These effects were mediated by changes in the expression of coding genes to synthetic and metabolizing melatonergic enzymes. Thus, the pineal gland plays a role as a first-line structure to respond to the death of cells inside the brain by turning NAS into the darkness hormone.

Comparative effects of fentanyl versus morphine on platelet inhibition induced by ticagrelor in patients with ST-segment elevation myocardial infarction: Full results of the PERSEUS randomized trial.

BackgroundMorphine reduces absorption and delays action onset of potent oral P2Y12 receptor inhibitors in patients with ST-segment elevation myocardial infarction (STEMI). We sought to determine the differential effects of fentanyl compared to morphine on the pharmacodynamics and pharmacokinetics of ticagrelor in STEMI patients undergoing primary percutaneous coronary intervention (PCI).MethodsPERSEUS (NCT02531165) was a prospective, single-center, open-label, randomized controlled study. Patients with STEMI who required analgesia were randomly assigned in a 1:1 ratio to treatment with intravenous fentanyl or morphine after ticagrelor loading dose (LD) administration. The primary endpoint was platelet reactivity at 2 hours after ticagrelor LD assessed by P2Y12 reaction units (PRU).ResultsThe study was prematurely stopped in June 2017 after enrolment of 38 out of 56 planned patients. PRU at 2 hours following ticagrelor LD was 173.3 ± 89.7 in the fentanyl group and 210.3 ± 76.4 in the morphine group (p = 0.179). At 4 hours, PRU was significantly lower among patients treated with fentanyl as compared to those treated with morphine (90.1 ± 97.4 vs. 168.0 ± 72.2; p = 0.011). Maximal plasma concentrations of ticagrelor and its active metabolite AR-C124910XX tended to be delayed and numerically lower among patients treated with morphine compared to fentanyl. Total exposures to ticagrelor and AR-C124910XX within 6 hours after ticagrelor LD were numerically greater among patients treated with fentanyl compared to those treated with morphine.ConclusionsIn patients with STEMI undergoing primary PCI, fentanyl did not improve platelet inhibition at 2 hours after ticagrelor pre-treatment compared with morphine. Fentanyl may, however, accelerate ticagrelor absorption and increase platelet inhibition at 4 hours compared to morphine.

The role of CYP2C19 genotyping to guide antiplatelet therapy following ischemic stroke or transient ischemic attack

ABSTRACT Introduction Clopidogrel is an antiplatelet agent recommended for secondary prevention of ischemic stroke (IS) and transient ischemic attack (TIA). Conversion of clopidogrel to its active metabolite by hepatic cytochrome P450-2C19 (CYP2C19) is essential for the inhibition of the P2Y12 receptor and subsequent platelet aggregation to prevent thrombotic events. CYP2C19 is highly polymorphic, with over 30 loss of function (LoF) alleles. This review considers whether there is sufficient data to support genotype guided antiplatelet therapy after stroke. Areas covered A systematic literature review retrieved articles, which describe the interaction between CYP2C19 genotype and clinical outcomes following IS or TIA when treated with clopidogrel. The review documents efforts to identify optimal antiplatelet regimens and explores the value genotype guided antiplatelet therapy. The work outlines the contemporary understanding of clopidogrel metabolism and appraises evidence linking CYP2C19 LoF variants with attenuated platelet inhibition and poorer outcomes. Expert opinion There is good evidence that CYP2C19 LoF allele carriers of Han-Chinese ancestry have increased risk for further vascular events following TIA or IS when treated with clopidogrel. The evidence base is less certain in other populations. The expansion of pharmacogenetics into routine clinical practice will facilitate further research and help tailor other aspects of secondary prevention.

Comparison of ticagrelor and clopidogrel in the treatment of patients with coronary heart disease carrying CYP2C19 loss of function allele

BackgroundClopidogrel is a traditional P2Y12 receptor inhibitor that is widely used in clinical practice, but there are significant individual differences in its therapeutic effect. Carriers of the CYP2C19 deletion allele have a higher risk of adverse cardiovascular events than non-carriers.MethodsIn this study, 170 patients diagnosed with coronary heart disease (CHD) and on regular oral clopidogrel or ticagrelor antiplatelet therapy in the Department of Cardiology of Wuxi Second People’s Hospital from August to December 2019 were screened. Baseline patient data were collected, percutaneous coronary angiography (CAG) or coronary computed tomography angiography (CTA) results were recorded, CYP2C19 gene type was detected, and prognosis/outcome was assessed by telephone/outpatient/inpatient follow-up for 12 months.Results(I) Of the 170 patients, 0.66% were the fast metabolic type, 41.45% were the normal metabolic type, 42.76% were the intermediate metabolic type, and 15.13% were the poor metabolic type. CYP2C19*2 mutation accounted for 89.29% of all mutations, CYP2C19*3 mutation accounted for 9.82%, and CYP2C19*17 mutation accounted for only 0.89%. (II) Among the patients with CHD who regularly took clopidogrel, the risk in the intermediate metabolic group was 5.208-fold higher than that of normal metabolic group, and that of the poor metabolic group was 3.75-fold higher than that of normal metabolic group; there was no significant difference between the intermediate and poor metabolic groups. (III) Prognosis was significantly associated with regular use of ticagrelor or clopidogrel by patients in the intermediate metabolic group. There was no significant correlation between poor metabolism (PM) and normal metabolism (NM). Prognosis was significantly associated with regular use of ticagrelor or clopidogrel in patients undergoing percutaneous coronary intervention (PCI), but not in patients who did not undergo PCI.ConclusionsCYP2C19 polymorphism was associated with the prognosis of patients with CHD administered antiplatelet therapy with oral clopidogrel. The incidence of poor prognosis was significantly increased with CYP2C19*2 and/or CYP2C19*3 mutations, and patients undergoing PCI or carrying a single CYP2C19 deletion allele had a better prognosis with ticagrelor as replacement therapy.

Adenosine diphosphate‐induced aggregation is enhanced in platelets obtained from patients with thrombotic primary antiphospholipid syndrome (t‐PAPS): Role of P2Y12‐cAMP signaling pathway

BackgroundThrombotic antiphospholipid syndrome (t‐PAPS) is characterized by arterial, venous, or microvascular occlusions, which are explained, in part, by the presence of antiphospholipid (aPL) antibodies. Although there is much evidence indicating that isolated aPL antibodies increase the activity of platelets obtained from healthy volunteers, platelet function in t‐PAPS has not been as widely studied. ObjectiveTo evaluate platelet reactivity in t‐PAPS patients. MethodsPlatelet aggregation, protein expression, and cyclic nucleotide levels were carried out in platelet rich plasma (PRP) or washed platelets (WPs) obtained from t‐PAPS or healthy volunteers. ResultsADP‐induced aggregation was significantly higher in PRP obtained from t‐PAPS than obtained from the control. The protein expression of P2Y12 receptor and Gs alpha was significantly higher and lower, respectively in WPs from t‐PAPS patients. In PRP incubated with iloprost or sodium nitroprusside, the residual platelet reactivity induced by ADP was still higher in PRP from t‐PAPS than from the control. Lower intracellular levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) were observed in unstimulated PRP from t‐PAPS patients. The protein expression of soluble guanylate cyclase subunits and phosphodiesterases types 3 and 5 did not differ. The antiplatelet activity of ticagrelor was similar between the groups and cilostazol significantly potentiated this response. Isolated aPL antibodies obtained from t‐PAPS patients potentiated ADP‐induced aggregation in healthy platelets but did not affect the inhibitory responses induced by iloprost or sodium nitroprusside. ConclusionsThe overexpression of P2Y12 receptor, accompanied by lower levels of cAMP and cGMP levels produced greater amplitude of ADP aggregation in platelets from t‐PAPS patients.

Front Cover: A Collagen‐Derived Oligopeptide from Salmo salar Collagen Hydrolysates Restrains Atherogenesis in ApoE–/– Mice via Targeting P2Y12 Receptor

Mol. Nutr. Food Res. 2022, 66, 202200166 DOI: 10.1002/mnfr.202200166 Hyp-Gly-containing peptides are abundant in collagen hydrolysates of Salmo Salar. The peptide OGEFG inhibit platelet aggregation via antagonism effects on P2Y12 receptor to regulate Gβγi-PI3K-Akt and Gαi-cAMP-VASP signaling. Long-term administration of OGEFG significantly reduce atherosclerotic plaque formation without side effects in ApoE–/– mice, indicating the possibility to be developed as an effective diet supplement to prevent atherogenesis and thrombotic disease. This is reported by Bo Li and co-workers in article number 2200166.