Thromboxane B2 Levels Research Articles

Role of Thymus and Activation-Regulated Chemokine in Allergic Asthma.

BackgroundAsthma is a chronic inflammatory airway disease characterized by the predominant infiltration of inflammatory cells in the airways. Thymus and activation-regulated chemokine/C–C motif chemokine 17 (TARC/CCL17) is a chemokine responsible for trafficking T helper 2 cells into sites of allergic inflammation.ObjectiveTo validate the role of TARC in association with clinical and inflammatory parameters in adult asthmatics.MethodsWe enrolled 128 asthmatic patients and 70 healthy controls (HCs). Asthma-related clinical and laboratory parameters, including lung function and eosinophil counts, were measured. Serum levels of TARC, free immunoglobulin E (IgE), and eosinophil-derived neurotoxin (EDN) were determined by using enzyme-linked immunosorbent assay; serum total IgE level was measured using ImmunoCAP. The levels of inflammatory lipid mediators, such as leukotriene E4 (LTE4), 15-hydroxyeicosatetraenoic acid (15-HETE), thromboxane B2 (TXB2), and prostaglandin F2α (PGF2α), were measured by liquid chromatography-tandem mass spectrometry.ResultsSerum TARC levels are significantly higher in asthmatics than in HCs and in allergic asthmatics than in HCs (P < 0.010 for all), with significantly negative correlations between serum TARC levels and FEV1%/MMEF% values (r = −0.314, r = −0.268, P < 0.050 for both). The patients with higher serum TARC levels had higher levels of serum total and free IgE levels (P < 0.050 for both) with positive correlations to serum levels of EDN, TXB2, and 15-HETE (r = 0.233, r = 0.264, and r = 0.223, respectively, P < 0.050 for all).ConclusionWe suggest the role of TARC in allergic asthma via contributing to mast cell and eosinophilic inflammation.

Metformin use in patients hospitalized with COVID-19: lower inflammation, oxidative stress, and thrombotic risk markers and better clinical outcomes.

Diabetes mellitus (DM) is associated with a greater risk of COVID-19 and an increased mortality when the disease is contracted. Metformin use in patients with DM is associated with less COVID-19-related mortality, but the underlying mechanism behind this association remains unclear. Our aim was to explore the effects of metformin on markers of inflammation, oxidative stress, and hypercoagulability, and on clinical outcomes. Patients with DM on metformin (n = 34) and metformin naïve (n = 41), and patients without DM (n = 73) were enrolled within 48 h of hospital admission for COVID-19. Patients on metformin compared to naïve patients had a lower white blood cell count (p = 0.02), d-dimer (p = 0.04), urinary 11-dehydro thromboxane B2 (p = 0.01) and urinary liver-type fatty acid binding protein (p = 0.03) levels and had lower sequential organ failure assessment score (p = 0.002), and intubation rate (p = 0.03), fewer hospitalized days (p = 0.13), lower in-hospital mortality (p = 0.12) and lower mortality plus nonfatal thrombotic event occurrences (p = 0.10). Patients on metformin had similar clinical outcomes compared to patients without DM. In a multiple regression analysis, metformin use was associated with less days in hospital and lower intubation rate. In conclusion, metformin treatment in COVID-19 patients with DM was associated with lower markers of inflammation, renal ischemia, and thrombosis, and fewer hospitalized days and intubation requirement. Further focused studies are required to support these findings.

The antithrombosis effect of dehydroandrographolide succinate: in vitro and in vivo studies

Context Dehydroandrographolide succinate (DAS) is mainly used in the clinical treatment of various infectious diseases. Its potential effects on platelet aggregation and blood coagulation systems have not been reported systematically. Objective To explore whether DAS exerts an antithrombotic effect and its internal mechanism. Materials and methods Human blood samples and Sprague-Dawley (SD) rats divided into control, aspirin (30 mg/kg), and DAS groups (200, 400 and 600 mg/kg) were used to measure the platelet aggregation rate, coagulation function, coagulation factor activity, and contents of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1α (6-keto-PGF1α). The histopathology of the SD rat gastric mucosa was also observed. All rats were administered intragastric or intraperitoneal injections once a day for 3 consecutive days. Results Compared to control group, DAS significantly inhibited the platelet aggregation rate (ED50 = 386.9 mg/kg) by decreasing TXB2 levels (1531.95 ± 649.90 pg/mL to 511.08 ± 411.82 pg/mL) and activating antithrombin III (AT-III) (103.22 ± 16.22% to 146.46 ± 8.96%) (p < 0.05). In addition, DAS significantly enhanced the coagulation factors FV (304.12 ± 79.65% to 443.44 ± 75.04%), FVII (324.19 ± 48.03% to 790.66 ± 225.56%), FVIII (524.79 ± 115.47% to 679.92 ± 143.34%), FX (34.90 ± 7.40% to 102.76 ± 29.41%) and FXI (38.12 ± 10.33% to 65.47 ± 34.08%), increased the content of Fg (2.18 ± 0.39 to 3.61 ± 0.37 g/L), shorten the PT (10.42 ± 0.44 to 9.22 ± 0.21 s), APTT (16.43 ± 1.4 to 14.07 ± 0.75 s) and TT time (37.04 ± 2.13 to 32.68 ± 1.29 s) (p < 0.05), while the aspirin group showed no such effect on these items but showed reduced activity of FII (89.21 ± 21.72% to 61.83 ± 8.95%) and FVIII (524.79 ± 115.47% to 306.60 ± 29.96%) (p < 0.05). Histopathological changes showed aspirin-induced gastric mucosa haemorrhage and the protective effect of DAS in the gastric mucosa. Conclusions DAS is more suitable than aspirin in thromboprophylaxis treatment, which provides a reliable theoretical and experimental basis for its clinical application.

Antithrombotic Activity of Heparinoid G2 and Its Derivatives from the Clam Coelomactra antiquata.

Clam heparinoid G2 (60.25 kDa) and its depolymerized derivatives DG1 (24.48 kDa) and DG2 (6.75 kDa) prepared from Coelomactra antiquata have been documented to have excellent fibrinolytic and anticoagulant activity. In this study, to further explore the antithrombotic activity of G2, DG1 and DG2, azure A, sheep plasma, and clot lytic rate assays were used to determine their anticoagulant and thrombolytic activity in vitro. The results indicated that the anticoagulant titer of G2 was approximately 70% that of heparin and the thrombolytic activity of DG2 was greater than G2, DG1, and heparin activities. Moreover, in a carrageenan-induced venous thrombosis model, oral administration of G2 and DG1 each at 20 mg/kg and 40 mg/kg for 7 days significantly reduced blacktail thrombus formation, increased tissue-type plasminogen activator, fibrin degradation products, and D-dimer levels, decreased von Willebrand factor and thromboxane B2 levels, and restored phylum and genus abundance changes of intestinal bacteria. DG2 had no antithrombotic effect. At 20 mg/kg, G2, DG1, and heparin had comparable antithrombotic activities, and DG1 at 40 mg/kg had more muscular antithrombotic activity than G2. Thus, DG1 could be an antithrombotic oral agent owing to its more robust antithrombotic activity and lower molecular weight.

Qingwei San treats oral ulcer subjected to stomach heat syndrome in db/db mice by targeting TLR4/MyD88/NF-\u03baB pathway

BackgroundQingwei San (QWS), one of classic Chinese Medicine prescripts, has been widely used to treat stomach heat syndrome which manifests oral ulcer (OU), periodontitis and upper gastrointestinal bleeding for seven hundred years. However, the therapeutic effects of QWS on diabetic OU subjected to stomach heat syndrome are still ambiguous. In the study, we investigated the pharmacological mechanisms.MethodsThe main components of QWS aqueous extract were analyzed by LC–MS, and potential pathways of QWS targeting OU were predicted by network pharmacology. The db/db mice were administered with the decoction of dried Zingiber officinale Rosc. rhizome combined with NaOH cauterization to establish the model of diabetic OU subjected to stomach heat syndrome. Subsequently, the model mice were treated with QWS, and OU wound healing status were recorded. The pathological changes of gastric tissue and oral mucosa were evaluated using hematoxylin–eosin staining, and the morphology of collagen fibers in oral mucosa was assessed by Masson staining. The levels of thromboxane B2 (TXB2), 6-Keto-prostaglandin F1α (6-keto-PGF1α), interleukin-1 β (IL-1β), IL-2, IL-6, tumor necrosis factor-α (TNF-α), β-endorphin (β-EP) and 5-Hydroxytryptamine (5-HT) were determined by ELISA assay. The protein expressions of Toll-like receptor 4 (TLR4), TNF receptor associated factor 6 (TRAF6), myeloid differentiation factor 88 (MyD88), inhibitor of NF-κB alpha (IκΒα), p-IκΒα and nuclear factor kappa-B (NF-κB) p65 were measured by Western Blotting.ResultsA total of 183 compounds in QWS were identified by LC–MS, and identified 79 bioactive compounds corresponded to 269 targets and 59 pathways. QWS high-dose treatment significantly reduced the level of TXB2 and the ratio of TXB2/6-keto-PGF1α. Meanwhile, it improved mucosal pathological morphology, and reduced the area of OU and local edema. Simultaneously, the levels of TNF-α, IL-1β, IL-6, IL-2 and 5-HT, and the expressions of TLR4, TRAF6, MyD88, p-IκΒα and NF-κB p65 were decreased.ConclusionQWS treatment facilitates the healing of OU, ameliorates pathological morphologies of gastric and oral mucosa and decreases the levels of pro-inflammatory cytokines in db/db mice subjected to stomach heat syndrome, whose mechanism may be associated with the inhibition of TLR4/MyD88/NF-κB signaling pathway to exert anti-inflammatory effects.

The effect of continuous Jue tone intervention on blood pressure and vasoactive substances in hypertensive rats with a liver-fire hyperactivity pattern

Jue tone is a kind of sound, using 3-mi as the main tone, and is melodious, profound, makes people feel comfortable and pleasant. This study aimed to explore the probable mechanism of Jue tone to reduce blood pressure (BP) in hypertensive rats with a liver-fire hyperactivity pattern by observing changes in BP as well as physiochemical indexes in plasma. Sixteen male spontaneous hypertensive rats (SHR) with a liver-fire hyperactivity pattern were randomly divided into a control group and a Jue tone group. The rats in the Jue tone group were treated with Jue tone (55–65 dB, played by the five elements of music rhythm instrument, a kind of physiotherapy regimen music played by Shen Wu) once a day for 4 weeks. The BP levels in each group were measured twice a week, on Monday and Friday. The levels of angiotensin II (Ang- II), thromboxane B2 (TXB2), endothelin-1 (ET-1), calcitonin gene-related peptide (cGRP), norepinephrine (NE), cortisol (CORT), and 5-hydroxytryptamine (5-HT). in plasma were detected by enzyme-linked immunosorbent assay after 4 weeks of intervention. BP and the levels of TXB2 and ET-1 in the plasma of the treatment group were significantly lower than those of the control group, while the level of cGRP was significantly higher. Jue tone can reduce the BP of hypertensive rats with a liver-fire hyperactivity pattern. The mechanism may correlate with a reduction in TXB2 and ET-1 and an increase in cGRP with the reduction of reactive oxygen species (ROS).

Yokukansan, a traditional Japanese medicine, suppresses stress-induced sympathetic activation and central responses to stress in rats

Stress exposure activates the sympathetic nervous system. We previously reported that restraint stress and stress-related neuropeptides increases plasma catecholamine levels and that brain prostanoids medicate these responses in rats. Yokukansan (YKS), a traditional Japanese medicine, has been used for neurosis, night crying and irritability. Additionally, it has been reported that YKS is also effective against the behavioral and psychological symptoms of dementia in patients with Alzheimer&apos;s disease, stress-related anxiety-like behavior and stress-induced increase in plasma corticosterone in rodents. These previous findings raise the possibility that YKS can exert its action in the brain and has suppressive effects on stress responses. In this study, we examined effects of YKS on stress-induced sympathetic activation and stress responses in the brain using rats. Repeated administration with YKS suppressed stress-induced increase in plasma adrenaline level. YKS also suppressed stress-induced elevation of prostaglandin E2 and thromboxane B2 levels in the paraventricular hypothalamic nucleus (PVN). In addition, YKS suppressed stress-induced increases of acetylcholine, GABA and serotonin in the PVN. Our results suggest that YKS can ameliorate stress-induced sympathetic activation via inhibition of stress responses in the brain.

Glycemic Control and Aspirin Resistance in Patients Taking Low-Dose Aspirin for Pre-eclampsia Prevention.

To assess the association between aspirin and glycemic control in diabetic, pregnant patients, and the risk for aspirin resistance in those with poor glycemic control across gestation taking low-dose aspirin (LDA) for pre-eclampsia (PEC) prevention. We performed a secondary analysis of samples collected during the Maternal-Fetal Medicine Units trial of LDA for PEC prevention. A subset of insulin-controlled diabetic patient samples on placebo or 60 mg aspirin daily were evaluated. Glycosylated hemoglobin was measured at randomization, mid-second trimester, and third trimester time points. Thromboxane B2 (TXB2) measurements were previously assessed as part of the original study. Primary outcome was the effect of LDA on glycosylated hemoglobin levels compared with placebo across gestation. Levels of glycosylated hemoglobin increased across gestation in the placebo group (2,067.7 [interquartile range, IQR: 1,624.6-2,713.5 µg/mL] vs. 2,461.9 [1,767.0-3,209.9 µg/mL] vs. 3,244.3 [2,691.5-4,187.0 µg/mL]; p < 0.01) compared with no difference in levels of glycosylated hemoglobin across gestation in the LDA group (2,186.4 [IQR: 1,462.3-3,097.7 µg/mL] vs. 2,337.1 [1,327.7-5,932.6 µg/mL] vs. 2,532.9 [1,804.9-5,511.8 µg/mL]; p = 0.78). Higher levels of glycosylated hemoglobin were associated with increased TXB2 levels prior to randomization (r = 0.67, p < 0.05). Incomplete TXB2 was higher in pregnancies with increasing levels of glycosylated hemoglobin compared with those with decreasing levels of glycosylated hemoglobin across gestation (69.2 vs. 18.1%, p = 0.02). LDA exposure may be beneficial to glycemic control in this patient population. Additionally, poor glycemic control is associated with a higher level of TXB2 in diabetic pregnant patients on LDA. Higher doses of aspirin may be required in these patients to prevent development of PEC. · Low-dose aspirin may improve glycemic control.. · Poor glycemic control increases risk for aspirin resistance.. · Higher doses of aspirin may be required for pre-eclampsia prevention..

Abstract 12228: Metformin Use in Patients Hospitalized With COVID-19: Lower Inflammation, Oxidative Stress, and Thrombotic Risk Markers and Better Clinical Outcomes

Introduction: Diabetes mellitus (DM) is associated with a greater risk of COVID-19 and an increased mortality when the disease is contracted. Metformin use in patients with DM is associated with less COVID-19-related mortality, but the underlying mechanism behind this association remains unclear. Hypothesis: We hypothesize that inhibitory effect of metformin on markers of inflammation, oxidative stress, and hypercoagulability is associate with better clinical outcomes. Methods: Patients with DM on metformin (n=34) and metformin naïve (n=41), and patients without DM (n=73) were enrolled within 48 hours of hospital admission and were diagnosed with COVID-19 by reverse transcription-polymerase chain reaction assay. Laboratory assessments were conducted within 48 hours of hospital admission. The chi-squared test was used to determine whether there was a significant difference in frequencies between disease groups; p&lt; 0.05 was considered a significant difference between groups. Results: DM patients on metformin compared to naïve patients had a lower white blood cell count (p=0.02), d-dimer (p=0.04), urinary 11-dehydro thromboxane B 2 (p=0.01) and urinary liver-type fatty acid binding protein (p=0.03) levels and had lower sequential organ failure assessment score (p=0.0002), intubation rate (p=0.03), and a trend for fewer hospitalized days (p=0.13), lower in-hospital mortality (p= 0.12) and lower mortality plus nonfatal thrombotic event occurrences (p=0.10). Patients on metformin had similar clinical outcomes compared to patients without DM. Conclusion: In conclusion, metformin treatment in COVID-19 patients with DM was associated with lower markers of inflammation, renal ischemia, and thrombosis; and fewer hospitalized days and intubation requirement. Further focused studies are required to support these findings.

Therapeutic effect of Xuezhitong capsule on microvascular angina

Purpose: To determine the therapeutic effect of Xuezhitong capsule in patients with microvascular angina (MVA), and its impact on vascular endothelial function.Methods: In total, 172 MVA patients treated in Beijing City Fengtai District Nanyuan Hospital from September 2017 to September 2019 were selected and randomized into control group which received conventional treatment, and treatment group which received Xuezhitong capsules plus. There were 86 patients in each group. Therapeutic effect, levels of inflammatory factors, i.e., high-sensitivity C- reactive protein (hs-CRP), interleukin-(IL-6), tumor necrosis factor-α (TNF-α), and vascular endothelial factors such as nitric oxide (NO), thromboxane B2 (TXB2) and endothelin (ET), were determined.Results: Markedly higher total treatment effectiveness was observed in the treatment group than in the control group (89.53 % vs. 72.94 %; p &lt; 0.05). In both groups, treatment reduced the levels of hs-CRP, IL-6, TNF-α, TXB2 and ET, but elevated NO, with better results for treatment group than the control group (p &lt; 0.05). Better optimizations of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein (HDL) were observed in the treatment group, relative to the control group (p &lt; 0.05). Patients in the treatment group experienced fewer (8.14%) adverse reactions than those in control group (21.18 %, p &lt; 0.05).Conclusion: Xuezhitong capsule, when combined with conventional treatment, exerts high therapeutic effectiveness and safety in MVA patients by inhibiting inflammatory reactions, optimizing endothelialfunction, reducing blood lipid levels, and decreasing the incidence of cardiovascular adverse events. Thus, the combination therapy is a potentially superior therapeutic strategy to the conventional approach for the management of MVA patients.

COX-2 pathway is upregulated in ultra-high risk individuals for psychosis

Background The identification of Ultra-High Risk (UHR) individuals is thought to be useful for early intervention to improve psychosis outcomes. However, transition rates vary widely, and there is an effort to make these criteria more specific and accurate. Neuroinflammation has been discussed in the pathophysiology of psychosis. The metabolism of eicosanoids is a key process in inflammatory states. Therefore, we investigated whether the study of the inflammatory COX-2 pathway through the quantification of the eicosanoid levels can be a useful approach for the characterisation of UHR individuals. Methods One hundred and twenty-two individuals were included in this study (67 UHR and 55 controls) based on performance on the Prodromal Questionnaire. UHR status was assessed by Structured Interview for Prodromal Syndromes (SIPS). We determined the levels of Prostaglandin F2α (PGF2α), Prostaglandin E2 (PGE2), and Thromboxane B2 (TxB2) in plasma using ELISA assays. Results Concentrations of PGE2 and TxB2 were increased in UHR compared to controls (p = 0.01 and p < 0.05, respectively). PGE2 and PGF2α levels were correlated to negative symptoms (p < 0.01 and p < 0.05), whereas TxB2 correlated with positive symptoms (p = 0.05) as assessed by the SIPS. Conclusions Our findings suggest that overactivation of the COX-2 pathway may be related to an increased risk for psychosis. However, our data do not allow us to draw conclusions related to the cause-effect mechanisms. Future studies should determine whether the levels of the eicosanoids have a predictive value for the transition of UHR to frank psychosis.

The Synergistic Effect of Ginkgo biloba Extract 50 and Aspirin Against Platelet Aggregation.

PurposeWe aimed to investigate potential synergistic antiplatelet effects of Ginkgo biloba extract (GBE50) in combination with aspirin using in vitro models.MethodsArachidonic acid (AA), platelet activating factor (PAF), adenosine 5ʹ-diphosphate (ADP) and collagen were used as inducers. The antiplatelet effects of GBE50, aspirin and 1:1 combination of GBE50 and aspirin were detected by microplate method using rabbit platelets. Synergy finder 2.0 was used to analyze the synergistic antiplatelet effect. The compounds in GBE50 were identified by UPLC-Q/TOF-MS analysis and the candidate compounds were screened by TCMSP database. The targets of candidate compounds and aspirin were obtained in TCMSP, CCGs, Swiss target prediction database and drugbank. Targets involving platelet aggregation were obtained from GenCLiP database. Compound-target network was constructed and GO and KEGG enrichment analyses were performed to identify the critical biological processes and signaling pathways. The levels of thromboxane B2 (TXB2), cyclic adenosine monophosphate (cAMP) and PAF receptor (PAFR) were detected by ELISA to determine the effects of GBE50, aspirin and their combination on these pathways.ResultsGBE50 combined with aspirin inhibited platelet aggregation more effectively. The combination displayed synergistic antiplatelet effects in AA-induced platelet aggregation, and additive antiplatelet effects occurred in PAF, ADP and collagen induced platelet aggregation. Seven compounds were identified as candidate compounds in GBE50. Enrichment analyses revealed that GBE50 could interfere with platelet aggregation via cAMP pathway, AA metabolism and calcium signaling pathway, and aspirin could regulate platelet aggregation through AA metabolism and platelet activation. ELISA experiments showed that GBE50 combined with aspirin could increase cAMP levels in resting platelets, and decreased the levels of TXB2 and PAFR.ConclusionOur study indicated that GBE50 combined with aspirin could enhance the antiplatelet effects. They exerted both synergistic and additive effects in restraining platelet aggregation. The study highlighted the potential application of GBE50 as a supplementary therapy to treat thrombosis-related diseases.

Efficacy and Safety of Text Messages Targeting Adherence to Cardiovascular Medications in Secondary Prevention: TXT2HEART Colombia Randomized Controlled Trial.

BackgroundAtherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide, with a prevalence of approximately 100 million patients. There is evidence that antiplatelet agents and antihypertensive medications could reduce the risk of new vascular events in this population; however, treatment adherence is very low. An SMS text messaging intervention was recently developed based on behavior change techniques to increase adherence to pharmacological treatment among patients with a history of ASCVD.ObjectiveThis study aims to evaluate the efficacy and safety of an SMS text messaging intervention to improve adherence to cardiovascular medications in patients with ASCVD.MethodsA randomized controlled clinical trial for patients with a prior diagnosis of cardiovascular events, such as acute myocardial infarction, unstable angina, cerebrovascular disease, or peripheral artery disease, in one center in Colombia was conducted. Patients randomized to the intervention arm were assigned to receive SMS text messages daily for the first 4 weeks, 5 SMS text messages on week 5, 3 SMS text messages each in weeks 6 and 7, and 1 SMS text message weekly from week 8 until week 52. In contrast, patients in the control arm received a monthly SMS text message reminding them of the next study appointment and the importance of the study, requesting information about changes in their phone number, and thanking them for participating in the study. The primary endpoint was the change in low-density lipoprotein cholesterol (LDL-C) levels, whereas the secondary endpoints were the changes in thromboxane B2 levels, heart rate, systolic and diastolic blood pressure, medication adherence, cardiac and noncardiac mortality, and hospitalization. Linear regression analyses and bivariate tests were performed.ResultsOf the 930 randomized patients, 805 (86.5%) completed follow-up and were analyzed for the primary endpoint. There was no evidence that the intervention changed the primary outcome (LDL-C levels; P=.41) or any of the secondary outcomes evaluated (all P>.05). There was also no evidence that the intervention was associated with adverse events.ConclusionsIn this study, there was no evidence that a behavior modification intervention delivered by SMS text messaging improved LDL-C levels, blood pressure levels, or adherence at 12 months. More research is needed to evaluate whether different SMS text messaging strategies, including personalized messages and different timings, are effective; future studies should include mixed methods to better understand why, for whom, and in which context (eg, health system or social environment) SMS text messaging interventions work (or not) to improve adherence in patients with ASCVD.Trial RegistrationClinicalTrials.gov NCT03098186; https://clinicaltrials.gov/ct2/show/NCT03098186International Registered Report Identifier (IRRID)RR2-10.1136/bmjopen-2018-028017

Increased Epoxyeicosatrienoic Acids and Hydroxyeicosatetraenoic Acids After Treatment of Iodide Intake Adjustment and 1,25-Dihydroxy-Vitamin D3 Supplementation in High Iodide Intake-Induced Hypothyroid Offspring Rats.

Aim: This study aimed to investigate the potential role of fatty acids in high iodide intake–induced hypothyroidism and its complications and also in the intervention of iodide intake adjustment and 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] supplementation.Methods: Pregnant rats were allocated to two groups, namely, normal iodide (NI, 7.5 μg/day) intake and 100 times higher-than-normal iodide (100 HI, 750 μg/day) intake. The offspring were continuously administered potassium iodide from weaning [i.e., postnatal day 21 (PN21)] to PN90. After PN90, the offspring were either administered iodide intake adjustment (7.5 μg/day) or 1,25(OH)2D3 supplementation (5 μg·kg−1·day−1), or both, for 4 weeks. Thyroid function tests (free triiodothyronine, free thyroxine, thyrotropin, thyroid peroxidase antibody, and thyroglobulin antibody), blood lipids (triglyceride, total cholesterol, free fatty acid, and low-density lipoprotein cholesterol), and vitamin D3 (VD3) levels were detected by ELISA. Cardiac function was measured by echocardiography. Blood pressure was measured using a non-invasive tail-cuff system. The serum fatty acids profile was analyzed by liquid chromatography–mass spectrometry.Results: In the offspring rats with continued 100 HI administration, the levels of 8,9-dihydroxyeicosatrienoic acid (8,9-DHET) and thromboxane B2 (TXB2) were decreased, while those of prostaglandin J2 (PGJ2), prostaglandin B2 (PGB2), 4-hydroxydocosahexaenoic acid (4-HDoHE), 7-HDoHE, 8-HDoHE, and 20-HDoHE were increased. Significant correlations were found between PGB2, 8,9-DHET, 7-HDoHE levels and thyroid dysfunction, between PGJ2, 20-HDoHE, PGB2, 8,9-DHET levels and cardiac dysfunction, between PGJ2, 20-HDoHE levels and hypertension, between 4-HDoHE, 8-HDoHE, TXB2 levels and dyslipidemia, and between PGB2 and decreased VD3 level. After the treatment of iodide intake adjustment and 1,25(OH)2D3 supplementation, the levels of 16-hydroxyeicosatetraenoic acids (16-HETE), 18-HETE, 5,6-epoxyeicosatrienoic acid (5,6-EET), 8,9-EET, 11,12-EET, 14,15-EET, PGE2, 5-oxo-ETE, and 15-oxo-ETE were increased. The significant associations between PGE2, 16-HETE, 18-HETE and improved thyroid function and also between 5,6-EET, 11,12-EET, 14,15-EET, 16-HETE, 15-oxo-ETE and attenuated dyslipidemia were detected.Conclusion: Increased levels of prostaglandins (PGs) and HDoHEs and decreased levels of 8,9-DHET and TXB2 might occur in the progression of cardiac dysfunction, hypertension, and dyslipidemia in high iodide intake–induced hypothyroidism. The increased levels of EETs and HETEs might help to ameliorate these complications after iodide intake adjustment and 1,25(OH)2D3 supplementation.

Levels of 15‐HETE and TXB2 in exhaled breath condensates as markers for diagnosis of childhood asthma and its therapeutic outcome

AbstractBackgroundDysregulation of eicosanoids is associated with asthma and a composite of oxylipins, including exhaled leukotriene B4 (LTB4), characterizes childhood asthma. While fractional exhaled nitric oxide (FeNO) has been used as the standard for monitoring steroid responsiveness, the potential utility of eicosanoids in monitoring the therapeutic outcomes remains unclear. We aimed to examine the levels of major eicosanoids representing different metabolic pathways in exhaled breath condensates (EBCs) of children with asthma during exacerbation and after treatment.MethodsLevels of 6 exhaled eicosanoid species in asthmatic children and healthy subjects were evaluated using ELISA.ResultsIn addition to those previously reported, including LTB4, the levels of exhaled 15‐hydroxyeicosatetraenoic acid (15‐HETE), but not thromboxane B2 (TXB2), showed significant difference between asthmatics (N = 318) and healthy controls (N = 97), particularly the severe group showed the lowest levels of exhaled 15‐HETE. Receiver operating characteristic (ROC) curve analyses revealed similar distinguishing power for the levels of 15‐HETE, FEV1 (forced expiratory volume in the first second), and FeNO, while the 15‐HETE/LTB4 ratio was significantly lower in subjects with asthma as compared to that of healthy controls (p &lt; 0.0001). Analysis of asthmatics (N = 75) during exacerbation and convalescence showed significant improvement in lung function (FEV1, p &lt; .001), but not FeNO, concomitant with significantly increased levels of 15‐HETE (p &lt; .001) and reduced levels of TXB2 (p &lt; .05) at convalescence, particularly for those who at the top 30% level during exacerbation. Further, decreased LTB4 and lipoxin A4 (LXA4) at convalescence were noted only in those at the top 30 percentile during exacerbation.ConclusionThe exhaled 15‐HETE was found to discriminate childhood asthma while decreased levels of exhaled TXB2 and increased levels of 15‐HETE were prominent at convalescence.

Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors Reduce Platelet Activation Modulating ox-LDL Pathways.

Background: Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. Methods: In a multicenter before–after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Results: Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 (p < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. Conclusions: PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.

Abstract 34: High urinary thromboxane B2 associates with lethal prostate cancer in African American men and inversely correlates with aspirin use

Abstract Background: Systemic low-grade inflammation is a candidate risk factor for prostate cancer (PC) in African American (AA) men, potentially contributing to lethal PC development. We previously reported that regular aspirin use is associated with a decreased risk of advanced stage disease and disease recurrence in AA patients with PC. The cancer-preventive benefits of aspirin have been attributed to inhibition of the cyclooxygenase (COX) pathway. Thromboxane A2 (TXA2) is an eicosanoid produced by the COX1 enzyme in platelets. Aspirin can inhibit metastasis by inhibiting COX1 activity and TXA2 synthesis. Hence, we assessed the role of TXA2 in the development of lethal PC. Because TXA2 is unstable, we measured its corresponding primary metabolite, urinary thromboxane B2 (TXB2), to examine the relationship of TXA2 with PC. Method: TXB2 was measured in cases (977) and controls (1022) from the NCI-MD PC Case-Control study using a mass-spectrometry-based assay. TXB2 levels were modeled into low (≤median) and high (&amp;gt;median) levels. We calculated risk factor-adjusted odds ratios (ORs) and 95% confidence intervals (CI) using unconditional logistic regression, adjusted hazard ratios (HR) using Cox regression and sub hazard ratios (SHR) using the Fine-Gray model. Results: We observed increased TXB2 levels in cases and an inverse relationship between levels of TXB2 and aspirin use in both cases and controls. For cases who used aspirin, the odds of having high TXB2 were reduced when compared to non-users (OR 0.46 95%CI, 0.34-0.61). This observation remained significant when stratified by race/ethnicity (AA: OR 0.36 95%CI, 0.23-0.54; EA: OR 0.58 95%CI, 0.38-0.88), indicating significant inhibition of TXB2 formation by aspirin, most notably in AA men. Further analysis showed that high TXB2 is associated with a PC case status in AA men (OR 1.44 95%CI, 1.08-1.93) but not EA men (OR 1.07 95%CI, 0.83-1.93), indicating increased TXA2 synthesis in AA men with PC compared to AA men without the disease. Also, men with high TXB2 were more likely to be diagnosed with metastasis compared to men with low TXB2 (OR 4.27 95%CI, 1.48-12.29), indicating more aggressive disease for cases with high TXB2. Furthermore, high TXB2 was associated with all-cause mortality (HR 1.56 95%CI, 1.05-2.33) and PC mortality (HR 4.02 95%CI, 1.46-11.07; SHR 2.89 95%CI, 1.03-8.11) in AA men only. Our findings indicate a distinct association between TXA2 and PC outcomes in AA men. Conclusion: Aspirin use inversely associates with high TXB2. This is of clinical interest as we report that increased TXB2 associates with PC in AA men, with aggressive PC, and with PC death which disproportionally affects AA men. This is consistent with our previous findings that aspirin may reduce lethal PC in AA men and highlights the potential benefit of aspirin for prevention of lethal PC in this high-risk group of men through inhibition of TXA2 synthesis. Citation Format: Maeve Bailey-Whyte, Ginger Milne, Tsion Z. Minas, Tiffany H. Dorsey, Wei Tang, Cheryl J. Smith, Michael B. Cook, Clayton Yates, Stefan Ambs. High urinary thromboxane B2 associates with lethal prostate cancer in African American men and inversely correlates with aspirin use [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 34.

Lower Antiplatelet Effect of Aspirin in Essential Thrombocythemia than in Coronary Artery Disease.

Background Patients with essential thrombocythemia (ET) and coronary artery disease (CAD) have increased risk of thromboembolic complications. In addition, a reduced antiplatelet effect of aspirin has been demonstrated in both patient groups. As ET is a platelet disorder, platelets may be more important for the thromboembolic risk in ET than in CAD. We aimed to investigate the antiplatelet effect of aspirin and platelet turnover in ET versus CAD patients. Methods We included 48 ET patients and an age-matched group of 48 CAD patients. The effect of aspirin was evaluated by thromboxane B 2 (TXB 2 ) levels and platelet aggregation. Platelet turnover was assessed by immature platelet count (IPC) and immature platelet fraction (IPF). Results ET patients had reduced effect of aspirin compared with CAD patients, demonstrated by significantly higher TXB 2 levels (median of differences = 22.3 ng/mL, p < 0.0001) and platelet aggregation (median of differences = 131.0 AU*min, p = 0.0003). Furthermore, ET patients had significantly higher IPC ( p < 0.0001) and IPF ( p = 0.0004) than CAD patients. Conclusion ET patients have lower 24-hour antiplatelet effect of aspirin than CAD patients. This may be explained by an increased platelet production and turnover counteracting the antiplatelet effect of aspirin. These findings strengthen the rationale for exploring novel antiplatelet regimens in ET patients to reduce the risk of cardiovascular events.

Relationship between the changes in thromboxane B2, 6-keto-prostaglandin Fla, and blood glucose levels and progressive ischemic stroke.

Progressive ischemic stroke is a common cerebrovascular disease with high morbidity. This study aimed to investigate the relationship between changes of Thromboxane B2 (TXB2), 6-keto-prostaglandin Fla (6-k-PGFla), and blood glucose (BG) levels with progressive ischemic stroke. A total of 106 patients with progressive ischemic stroke admitted to our hospital from December 2016 to December 2018 were recruited as the observation group, and 110 patients who received physical examination in our hospital during the same period were selected as the control group. The levels of TXB2, 6-k-PGFla, and BG in different groups were compared, the related risk factors affecting the prognosis of patients with progressive ischemic stroke were analyzed, and the receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of TXB2, 6-k-PGFla, and BG for the prognostic mortality of patients with progressive ischemic stroke. The levels of TXB2, 6-k-PGFla, and BG in the observation group were significantly higher than those in the control group (P<0.05). The prognostic mortality of participants with abnormally increased expression of TXB2, 6-k-PGFla, and BG was significantly higher than that of patients with normal expression of TXB2, 6-k-PGFla, and BG (P<0.05). Hypertension, diabetes, collateral circulatory disorders, hyperlipidemia, TXB2 (abnormal increase), 6-k-PGFla (abnormal increase), and BG (abnormal increase) were risk factors affecting the prognosis of patients with progressive ischemic stroke (P<0.05). The area under the curve (AUC) of the ROC curve showed that TXB2, 6-k-PGFla, BG, and the combination of them were 0.846, 0.893, 0.835, and 0.971, respectively, showing that the AUC of the combination of them was the largest. Hypertension, diabetes, collateral circulatory disorders, hyperlipidemia, TXB2 (abnormal increase), 6-k-PGFla (abnormal increase), and BG (abnormal increase) are risk factors affecting the prognosis of patients with progressive ischemic stroke. The combined detection of the 3 indicators showed high sensitivity and specificity in evaluating the prognostic mortality of patients with progressive ischemic stroke, indicating that clinicians might improve the early diagnosis rate of progressive ischemic stroke by combining the detection of TXB2, 6-k-PGFla, and BG to predict the prognosis of patients.

Anti-hyperlipidemic effects of the compound Danshen tablet: roles of antioxidation, anti-inflammation, anticoagulation, and anti-apoptosis

BackgroundHyperlipidemia could cause some serious harm to human health diseases, such as atherosclerosis, coronary heart disease. This study sought to investigate the effects of the compound Danshen tablet (CDT) on hyperlipidemia induced by a high-fat diet in ApoE−/− mice and related antioxidation, anti-inflammation, anticoagulation, and anti-apoptosis mechanisms.MethodsThe control group (Group 1) comprised 15 male C57BL/6N mice, and the other 5 groups (Groups 2–6) comprised 75 male ApoE−/− mice. These 75 mice were randomly divided into 1 of the following 5 groups: Group 2, a model group; Groups 3–5, the CDT groups, each of which was administered 375, 750, or 1,500 mg/kg of CDT; and Group 6, an atorvastatin group, which was administered 5.2 mg/kg of atorvastatin. All the mice were fed a high-fat diet for 16 weeks and intragastrically administered with CDT or atorvastatin once a day according to their body weight. After 16 weeks, serum was collected, the aorta was isolated, and blood lipid levels were detected. An enzyme-linked immunosorbent assay was used to detect the serum levels of 4-hydroxynonenal (4-HNE), 8-hydroxy-2'-deoxyguanosine (8-OHdG), intercellular adhesion molecule 1 (ICAM-1), monocyte chemoattractant protein 1 (MCP-1), thromboxane B2 (TXB2), tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1). The thickness of the aortic wall was measured by ultrasonography. Atherosclerotic plaque and endothelial cell apoptosis in the aortic root were evaluated using oil red O staining and terminal dUTP nick-end labeling (TUNEL) assays, respectively.ResultsA comparison of mice in the CDT group and mice in the model group showed that CDT significantly inhibited mice’s weight gain. CDT reduced the levels of the inflammatory factor ICAM-1 and the oxidative damage molecule 4-HNE. In the coagulation system, CDT significantly increased tPA levels and reduced TXB2 and PAI-1 levels. Ultrasonography showed that CDT increased the thickness of the aortic wall. The oil red O staining results revealed that CDT significantly ameliorated lipid accumulation in the aortic valve. TUNEL assays indicated that CDT reduced the number of TUNEL-positive cells in the aortic valve.ConclusionsCDT has a certain protective effect on hyperlipidemia. The mechanism of CDT may be related to antioxidation, anti-inflammation, anticoagulation, and anti-apoptosis.