bluuebunny/crossref_metadata_2025_split huggingface dataset:
RGS10 serves as a braking system for platelet hyperactivity
Authors: Hensch Nicole R , Karim Zubair A , Qasim Hanan , Khasawneh Fadi T 
Published: November 2023

Regulators of G protein signaling (RGS) proteins act as GTPase activating proteins to negatively regulate G protein‐coupled receptor (GPCR) signaling. Although several RGS proteins including RGS2, RGS16, RGS10, and RGS18 are expressed in human and mouse platelets, the respective unique function(s) of each have not been fully delineated. RGS10 is a member of the D/R12 subfamily of RGS proteins and is expressed in microglia, macrophages, megakaryocytes, and platelets. We used a genetic approach to examine the role(s) of RGS10 in platelet activation in vitro and hemostasis and thrombosis in vivo. GPCR‐induced aggregation, α‐granule secretion, and integrin activation were much more pronounced in platelets from Rgs10−/− mice relative to wild type (WT). Accordingly, these mice had markedly reduced bleeding times and were more susceptible to vascular injury‐associated thrombus formation than control mice. These findings suggest a unique, non‐redundant role of RGS10 in modulating the hemostatic and thrombotic functions of platelets in mice. RGS10 thus represents a potential therapeutic target to control platelet activity and/or hypercoagulable states.Support or Funding InformationThis research was supported by funds provided by the College of Pharmacy at Western University of Health Sciences (to F.T.K). This work has been approved by Institutional Review Board and the Institutional Animal Care and Use Committee at Western University of Health Sciences, as applicable.
A Prospective, Open Label Study to Evaluate the Pharmacokinetics of Dabigatran in Patients With Non‐Valvular Atrial Fibrillation and Severe Renal Impairment Who Are Receiving Dabigatran Etexilate (75 mg twice daily)
Authors: Martin Jack , Esmaeili Habib , Manuel Raymond C. , Petrini Michaela , Wiebe Sabrina , Maas Hugo 
Published: November 2023

IntroductionDabigatran etexilate (DE) is a direct oral thrombin inhibitor. Dabigatran excretion is 80% renal, and exposure increases with the severity of renal failure. The FDA approved DE 75 mg BID for non‐valvular atrial fibrillation (NVAF) patients with severely impaired renal function (SIRF), defined as a CrCl of 15–30mL/min, based on post‐hoc pharmacokinetic (PK) modelling.ObjectivesTo assess dabigatran exposure at both trough and peak levels in patients with NVAF and SIRF, who were receiving DE 75 mg BID.MethodsPatients received DE (75 mg BID) for at least 7 days before 2 blood samples were obtained; the first at 10–16 hrs post‐dose (immediately prior to next dose) for Cpre,ss (steady state predose; trough), and the second 2 hrs (±30 min) post‐dose for C2,ss (steady state 2 hrs post‐dose; expected peak). Pharmacodynamic effect parameters at Ebase (pre‐DE; baseline), Epre,ss (steady state predose; trough), and E2,ss (steady state 2 hrs post‐dose; expected peak) were assessed by established coagulation assays (aPTT, dTT, ECT and TT).ResultsOf 150 patients screened, 60 were treated; 40% were male, 78.3% white, and their median age was 84. Reported Cpre,ss values (N=51) and variability were mostly in the predicted ranges of the PK model, with a gMean of 155 ng/mL, a gCV of 76.9%, and a range of 15.6 to 498 ng/mL. The C2,ss gMean value (N=59) was 202 ng/mL, with a gCV of 70.6%, and a range of 42.0 to 680 ng/mL. The pharmacodynamic effects of dabigatran on coagulation assays are presented in Table 1. Five patients reported bleeding events during the trial, all of which were considered to be minor bleeds by the investigators.ConclusionsThe levels of dabigatran exposure reported here in patients with NVAF and SIRF largely confirmed earlier PK predictions (Lehr et al. J Clin Pharmacol. 2012 Sep;52(9):1373–8), supporting the use of 75 mg DE BID in this patient group. Relationships between plasma dabigatran levels and coagulation assay results were also in line with earlier studies.Support or Funding InformationBoehringer Ingelheim Pharmaceuticals, Inc. funded the study, and provided support for medical writing and editorial support. The authors did not receive any direct payment for the writing of this abstract.

aPTT
ECT
dTT
TT

N*

60
59
60
31

Ebase
s†(SD)
43.1(12.5)
67.7(36.1)
43.9(14.7)
49.4(73.3)

Epre,ss
s(SD)
52.3(10.9)
96.0(37.6)
54.2(12.9)
154.0(66.0)

E2,ss
s(SD)
61.3(35.6)
117.0(50.8)
60.0(16.6)
153.0(51.8)

aPTT, activated prothrombin time; dTT, dilute thrombin time; ECT, ecarin clotting time; s, seconds; SD, standard deviation; TT, thrombin time
N displayed is maximal N; E, effect; Epre,ss and E2,ss were calculated with slightly smaller Ns. All values include samples from both treatment naїve and pre‐treated patients.
values presented are arithmetic means.
12‐HETrE Exerts its Antithrombotic Effects Through the Prostacyclin Receptor
Authors: Tourdot Benjamin , Isingizwe Zitha , Adili Reheman , Holman Ted , Holinstat Michael 
Published: November 2023

The antithrombotic effect of dihomo‐γ‐linolenic acid (DGLA), an ω‐6 fatty acid, was recently shown to be dependent upon 12‐lipoxygenase (12‐LOX) and its DGLA‐derived metabolite, 12‐hydroxy‐eicosatrienoic acid (12‐HETrE). 12‐HETrE inhibits platelet activation via the Gαs signaling pathway; however, the Gαs‐coupled receptor by which 12‐HETrE mediates its antiplatelet effects has yet to be identified. We hypothesized that 12‐HETrE exerts its antiplatelet effects through a known lipid binding Gαs‐coupled prostanoid receptor expressed by platelets: IP, EP2, EP4, or DP1. In this study, we found that pharmacological inhibition of the IP receptor reduced 12‐HETrE's antiplatelet effects in humans, while genetic ablation of the IP receptor in murine platelets completely abolished the inhibitory effects of 12‐HETrE. Consistent with our in vitro studies, 12‐HETrE's antithrombotic effects were abolished in IP receptor deficient mice. Further, ectopic expression of the IP receptor in Jurkat cells was sufficient for 12‐HETrE to induced Gαs signaling. Together this data demonstrates that 12‐HETrE's antiplatelet effects are at least partially dependent on IP receptor signaling. Importantly, this work identified a new class of endogenous IP receptor agonist that will aid in the rationale design of novel IP receptor therapeutics. Additionally, this study provides further knowledge of the mechanism by which DGLA supplementation inhibits platelets function.Support or Funding InformationThis work was funded in part through the National Institutes of Health grants R01 GM105671 (MH & TRH), R01 HL114405 (MH & TRH), R01 MD 007880 (MH), R01 AG047986 (MH & TRH), and F32 HL129491 (BET), as well as the University of Michigan Frankel Cardiovascular Center Summer Fellowship Program (ZRI).
Effect of Sevoflurane plus Ondansetron and Ranitidine vs. Propofol and Remifentanil for the Prevention of Post‐operative Nausea and Vomiting
Authors: Lynch Sharlette M , Tulp Orien L , Einstein George P 
Published: November 2023

Postoperative nausea and vomiting (PONV) are frequent and distressing complications following anesthesia [AN] and general surgery [GS]. The purpose of this study was to compare total intravenous AN (TIVA) using propofol and remifentanil [TIVA‐PR] vs. sevoflurane with prophylactic ondansetron and ranitidine [TIVA‐SF group] for the prevention of PONV. Hemodynamic changes [heart rate [HR] blood pressure [BP], and the quality of recovery such as post‐operative pain [POP] were compared between the two groups. Patients [n=60] undergoing AN and GS were randomly assigned to one of two prophylactic interventions [n=30/group]: (1) ondansetron 4 mg and ranitidine 50 mg before the induction of sevoflurane anesthesia [TIVA‐SF] group); and (2) propofol at 50–150 mcg/kg/minute + remifentanil 0.1 mcg/kg/min; (TIVA‐PR group). PONV incidence and severity was monitored immediately after GS for 24 hours. Recovery was assessed with a simulated wake up test and a simple behavioral score to assess overall recovery. The POP was assessed in each group via the visual analogue scale (VAS). The incidence of PONV was similar in the TIVA‐SF and TIVA‐PR groups during the 24 hours post GS [pGS], [TIVA‐SF=30.0%; TIVA‐PR 33.0%]. pGS HR was similar in both groups, but the GS mean arterial pressure (MAP) was significantly lower after induction and higher during surgical incision in the TIVA group [TIVA‐PR > TIVA‐SF, P<0.05]. The MAP in the TIVA‐PR was better controlled throughout GS than in TIVA‐ SF [MAP TIVA –PR < TIVA‐ SF, p<0.05]. The mean pain rating [MPR] was 3.5±3.4 in the TIVA‐PR group and 5.4±2.9 in TIVA‐ SF, while MPR was 3.1±3.1 in the TIVA‐PR group and 5.6±1.6 in the TIVA‐SF group. In the TIVA‐PR group, 8 out of 30 patients reported a pain score [PS] > 4; In the TIVA‐SF group, 18 out of 30 patients reported a PS > 4. In conclusion, IV ranitidine and ondanestron immediately before induction of TIVA using SF resulted in a similar reduction in PONV in comparison to TIVA‐PR. The overall PS recovery and HR did not differ significantly in both groups. The MAP demonstrated a significant increase after intubation in both the TIVA‐SF and TIVA‐PR groups, but was lower in TIVA‐PR group throughout the remainder of surgery. Upon emergence from anesthesia, the POP, behavioral scores, and the pGS recovery time were similar in both groups, but indicate that MAP was better controlled during GS with the TIVA‐PR than the TIVA‐ SF regimen.Support or Funding InformationSupported by Institutional Resources of USAT Colleges of Medicine and Graduate Studies and the Einstein Institute
Influences of Experimental Air Pollution on Human Sympathetic Nerve Traffic and Norepinephrine Metabolism: A Double Blind, Randomized, Twofold Crossover Study
Authors: Tank Jens , Heusser Karsten , Holz Olaf , May Marcus , Brinkmann Julia , Diedrich André , Framke Theodor , Koch Armin , Grosshennig Anika , Sweep Fred C.G.J. , Koch Wolfgang , Krug Norbert , Jordan Jens , Hohlfeld Jens 
Published: November 2023

BackgroundMuch of the evidence linking air pollutant exposure with changes in human cardiovascular autonomic regulation relied on epidemiological studies, exposure estimates, and indirect autonomic nervous system measurements. We tested the hypothesis that in healthy older individuals, experimental exposure to fine particles increases sympathetic nervous system activity and more so with addition of ozone.Material and MethodsEighteen healthy participants (age >50 years) completed all study visits and were included in the final analysis. Participants were exposed to clean air (‘placebo’), ultrafine particles (UFP, 50μg/m3), and combination of UFP+ozone (250 ppb) for 3 hours combined with intermittent bicycle ergometer training in a randomized, three‐period, cross‐over, double‐blind fashion. Three hours following exposure, respiration, ECG, blood pressure, and muscle sympathetic nerve activity (MSNA) were continuously recorded at supine rest, during deep breathing, and during a Valsalva maneuver. Venous blood samples for plasma catecholamine measurements were taken at baseline. Induced sputum was obtained at the end of each study day.ResultsCombined exposure to ozone and UFP but not UFP alone caused a significant increase in sputum neutrophils and circulating leucocytes. We did not detect significant effects on blood pressure or heart rate. Resting MSNA was 47±12 with clean air, 47±14 with UFP, and 45±14 bursts/min with UFP+ozone. Maximum MSNA during Valsalva phase IIb was similar. Yet, with UFP+ozone plasma norepinephrine concentrations were significantly increased with concomitant reduction in the dihydroxyphenylglycol (DHPG)/norepinephrine ratio. Respiratory sinus arrhythmia and Valsalva ratio were unaffected by experimental air pollution.ConclusionExposure to ultrafine particles with or without ozone does not elicit clinically relevant changes in central sympathetic or parasympathetic activity in healthy older subjects. The paradoxical norepinephrine increase with UFP+ozone may be explained by reduced peripheral norepinephrine uptake and metabolism.Support or Funding InformationMM was funded by a grant from the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG, awarded to JJ: JO 284/8‐1). The German Aerospace Center (DLR) supported JT, KH, and MM (50 WB1117, 50WB1517).
Clinical Pharmacokinetics and Preclinical Pharmacodynamics of (+)‐Epicatechin on Cardiometabolic Endpoints
Authors: Villarreal Francisco , Moreno‐Ulloa Aldo , Ciaraldi Theodore , Best Brookie , Ramirez‐Sanchez Israel , Ceballos Guillermo , Dugar Sundeep , Schreiner George , Henry Robert 
Published: November 2023

We have previously reported on the capacity of the cacao flavanol (−)‐epicatechin to vigorously stimulate mitochondria biogenesis and beneficially impact metabolism. However, preliminary studies indicate that the (+) epimer form may be more potent. In the present study, we report on the pharmacokinetics (PK), partial pharmacodynamics (PD) and initial safety analysis of (+)‐epicatechin (Epi) using a Phase I study performed in pre‐diabetic subjects. Using a mouse model of diet‐induced obesity and insulin resistance we also provide PD evidence of the metabolic effects of (+)‐Epi vs. those of (+)‐catechin to determine if the effects observed correspond to class actions. For the Phase I PK study, subjects were provided a single incremental dose of (+)‐Epi using either 10, 30 or 100 mg in capsules. For the PD study, subjects were provided a single 30 mg dose/day for 7 days. In all subjects blood samples were collected and an assessment of standard safety measures were performed. Results indicate that incremental doses of (+)‐Epi increase the half life of blood metabolites ranging from ~2–6 h. Seven day dosing of prediabetic subjects leads to a trend in reducing blood glucose levels (p=0.053) and markers of inflammation. No adverse effects were reported and the compound was well tolerated. In obese‐insulin resistant animals, 2 weeks of dosing (0.003, 0.01, 0.03, 0.1 and 0.3 mg/kg/day by oral gavage) led to a dose dependent significant improvement in markers of metabolism (weight gain, glucose, cholesterol, triglycerides with doses as low as 0.01 mg/kg/day). (+)‐Catechin yielded no effects at 0.1 mg/kg/day. Overall results indicate that (+)‐Epi evidences a favorable PK and safety profile. The compound exerts a positive impact on metabolism which may link to enhanced mitochondrial bioenergetics. The effects noted are not due to antioxidant actions as (+)‐catechin yielded no effects.Support or Funding InformationNIH AT8310, DK9871, Cardero Therapeutics, Inc.
Pretreatment With Probenecid Downregulates Kidney Pendrin Expression and Potentiates Hydrochlorothiazde Diuresis in Rat
Authors: Barone Sharon , Xu Jie , Zahedi Kamyar , Soleimani Manoocher 
Published: November 2023

BackgroundConcomitant deficiency of the Na‐Cl co‐transporter (NCC) and pendrin leads to significant salt wasting. Probenecid is an inhibitor of the organic anion transporters in the kidney proximal tubule and enhances uric acid excretion. Probenecid is also an inhibitor of pendrin in mammary cells (AJP Endo/Metab, 2003). The diuretic effect of Hydrochlorothiazide (HCTZ), which is a specific inhibitor of NCC, is significantly blunted consequent to compensatory salt absorption by pendrin. The downregulation or inactivation of pendrin enhances the diuretic effect of HCTZ.HypothesisPre‐treatment with probenecid will downregulate pendrin, therefore leaving NCC as the main salt absorbing transporter in the distal nephron. These changes enhance the diuretic effect of HCTZ.ResultsMale Sprague Dawley rats (200–225 gm BW) were pre‐treated with probenecid, at 250 mg/kg/day IP for 6 days. Urine output increased from 9.5 ml to 13.8 ml /24 hr on day 6 of probenecid treatment (p<0.05, n=5). Treatment of rats with HCTZ alone (40 mg/kg) for 4 days caused a mild diuresis which did not achieve statistical significance. However, treatment of rats that were pretreated with Probenecid for 6 days with a combination of Probenecid plus HCTZ for 4 additional days increased the urine output by greater than 300% to 42.1 ml/day (p<0.001, n = 5) compared to Probenecid‐treated or HCTZ‐treated animals. The animals treated with Probenecid plus HCTZ developed significant volume depletion as judged by >3 fold increase in the expression of renin in their kidneys. Immunofluorscence studies demonstrated an ~80% reduction in pendrin expression in kidneys of rats treated with Probenecid. Probenecid treatment reduced HCTZ excretion by ~40% suggesting competition between probenecid and HCTZ for secretion via organic anion transporters in the proximal tubule. The impaired excretion of HCTZ was unlikely to be responsible for the profound diuresis by probenecid plus HCTZ.ConclusionDespite being considered a mild agent, we propose that HCTZ could be a potent diuretic when administered in individuals pre‐treated with probenecid. The treatment with probenecid should also prevent the generation of hyperuricemia by HCTZ.Support or Funding InformationMerit Review Award by Veterans Administration.Center on Genetics of Transport, University of Cincinnati
YiqiHuoxue decoction and its constituents inhibit the activation of platelets and thrombosis for the prevention and treatment of cardiovascular diseases
Authors: Wu Hong , Lei Zhen , Gao Shuibo , Han Lihua 
Published: November 2023

YiqiHuoxue decoction (YHD) is frequently used for the prevention and treatment of cardiovascular diseases. Previous studies have demonstrated that YHD can promote angiogenesis and reduce left ventricular remodeling. The present study further investigated the effects of both YHD and ethanol‐precipitated YHD (EYHD) on the activation of platelets and thromboxane B2 (TXB2) in vitro and thrombosis in vivo. The results showed that 20 mg/mL of YHD and 2–20 mg/mL of 75% EYHD inhibited adenosine diphosphate (ADP)‐induced platelet aggregation. Moreover, collagen‐induced platelet aggregation was significantly suppressed by 20 mg/mL YHD, 20 mg/mL of 50, 50–75, and 75% EYHD, and 2 mg/mL of 50–75 and 75% EYHD. Furthermore, rats administered with 4 mg/mL 75% EYHD displayed a marked reduction in collagen‐induced platelet aggregation at 2 h post‐administration. Meanwhile, we observed the effects of YHD and EYHD on bleeding and clotting time in rats, and on mesenteric arterial thrombosis in mice. Our data indicates that YHD and EYHD markedly prolonged the onset of thrombosis and led to a loose attachment of the thrombus with the vascular endothelium, albeit with no significant influence on their bleeding or clotting times. Finally, we found that YHD and EYHD markedly reduced the level of thromboxane B2 (TXB2) using washed platelets. In conclusion, YHD and EYHD can effectively inhibit arterial thrombosis in vivo due to antiplatelet activity, which may exert beneficial effects on the prevention and treatment of cardiovascular diseases.Support or Funding InformationThis work was financially supported by grants from the National Natural Science Foundation of China (Grant No. 81072968) and Collaborative Innovation Center of Henan University of Traditional Chinese Medicine
Effects of GLA Precursors Added to Atherogenic Diet on Platelet Insulin Sensitivity, Plasminogen Activator Activity and Atherogenic Plaque Development in Rabbits
Authors: Beard Elizabeth Letitia , Edupuganti Srilatha 
Published: November 2023

Maintaining rabbits on a diet containing 2%Cholesterol (Ch) for 4–6 weeks usually promotes development of hypercholesterolemia, diminished plasma plasminogen activator activity(PPA) and atherosclerotic plaque formation. Also tissue insulin sensitivity and tissue delta‐6‐desatuase (D‐6‐D) levels needed to convert cis cis linoleic acid(LA) to gamma linoleic acid (GLA) are lowered. GLA is a precursor for the anti‐atherogenic prostaglandin, Prostacyclin (PGE2) production in normal tissues.In this study, three groups of 5 New Zealand strain male rabbits were fed AD (2% Ch, 6%Corn Oil, 92% Purina Rabbit Chow) for an 8 week period.. In Group I – the AD Control animals‐ the rabbits were fed AD alone. Group II rabbits were fed AD supplemented with 5% LA and in Group III, the animals received AD with 5% PRO added. In blood plasma assays for plasminogen activator activity (PAA), mean PAA values found in Group I AD Control animals was 11.7 %. In the (LA+ AD) Group II samples, it was 15.7% and 16.6% in (PRO+AD)‐Group III assays. The mean for blood cholesterol levels was 689.9mg% in the Group I AD Controls and lowered to 612.4 mg% in the (LA+AD) Group II and 595.1 mg% in the (PRO+AD) Group III samples. Tissue insulin sensitivity was measured by assaying blood platelet glucose content after incubation with exogenous glucose and insulin. Group I AD Control platelets had a mean value of 219.2 mg% Glucose. In (LA+AD) Group II, it increased to 304.4 mg% and in (PRO+AD) Group III‐ platelets, the mean was 308.7mg%. Gas chromatographic analyses of the aortae assayed for Linoleic Acid levels found a mean of 2645 nmol/mg dry wt. in Group I AD controls, 4310nmol/mg for LA+AD Group II aortae and 4290nmol/mg in the PRO+AD Group III aortae. Assays for GLA levels in aortae from AD Group I gave 10.1 nmol/mg dry wt., for LA+AD Group II, the value was 172nmol/gm and for PRO+AD Group III‐ it was 540nmol/mg.Atherosclerotic plaque present in the wall of the aortae, estimated on a scale of 0–5, indicated the maximum aortal plaque development was 4.5 in AD Control Group I rabbits, 3.5 in LA+AD Group II and 2.5 in P RO+AD Group III aortae.Addition of linoleic acid and primrose oil to AD, appeared to reduce atherogenesis that follows feeding rabbits AD alone. Addition of LA and PRO to AD increased blood levels of fibrinolytic activity and tissue sensitivity to insulin. These supplements lowered blood cholesterol and increased tissue levels of LA and GLA opposing the effects of AD dieting lacking them. Addition of LA and PRO to AD dieted rabbits resulted in increased tissue GLA levels which serve as a precursor for synthesis of the antiatherogenic Prostacylin (PGE2) in tissues.Support or Funding InformationFunded by a grant from the American Heart Association