bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical evaluation of hop‐drug interactions using probe substrates of cytochrome P450 enzymes and a hop dietary supplement
Authors: Chen Luying , Tonsing‐Carter Alyssa , van Breemen Richard 
Published: November 2023

ObjectiveThe title states the study objective.MethodLow doses of an oral cocktail of caffeine, tolbutamide, dextromethorphan, and alprazolam (probes for metabolism by CYP1A2, CYP2C9, CYP2D6, and CYP3A4, respectively) were administered to peri‐ and post‐menopausal women at baseline and then again after consuming a hop dietary supplement twice daily for 14 days. Serial blood samples were drawn and analyzed for concentrations of each probe substrate drug over time, and concentration‐time curve values were compared. A Shimadzu Nexera UHPLC system with a Shimadzu LCMS‐8060 triple quadrupole mass spectrometer was used with CID and SRM for the quantitative analysis of all four probe substrates in serum. Concentration‐time curves and other pharmacokinetics parameters were calculated using WinNonlin software.ResultsAccording to our preliminary in vitro data, hop preparations containing prenylated flavonoids and chalcones have the potential to inhibit some cytochrome P450 enzymes especially CYP1A2 and members of the CYP2C family, possibly contributing to prolonged drug half‐lives and elevated serum concentrations when co‐administered with specific therapeutic agents. To evaluate these safety issues in the clinic, we tested a botanically authenticated and chemically and biologically standardized hop dietary supplement in 16 peri‐ and post‐menopausal women (ages 40–75) for possible interactions with the pharmacokinetics of four FDA‐approved drugs (caffeine, tolbutamide, dextromethorphan, and alprazolam) as probe substrates for cytochrome P450 enzymes using ultra high‐pressure liquid chromatography/tandem mass spectrometry (UHPLC‐MS/MS). However, in this clinical evaluation, no changes in drug metabolism were detected after treatment with the hop dietary supplement.ConclusionAlthough in vitro assays had predicted in vivo drug‐botanical interactions, preliminary clinical data suggest no clinically relevant interactions of hop dietary supplements with drug metabolism.Support or Funding InformationFunding was provided by the NIH Office of Dietary Supplements and the National Center for Complementary and Integrative Health (NCCIH) [P50 AT000155]
Using Gaming Strategies to Augment Pharmacology Content Retention in a Doctor of Pharmacy Program
Authors: Malhotra Ashim 
Published: November 2023

Objective1) To enhance learner engagement in acquisition of pharmaceutical science content at a three year pharmacy program using interactive games like Jeopardy! 2) Augment learner recall of fundamental concepts and information retrieval, targeting “cognitive functions” in Bloom's Taxonomy.MethodsThe Pacific University School of Pharmacy implements a three year curriculum where renal, immune, and cardiovascular pharmacology is taught in the P1 year. We implemented a gaming strategy to 1) capture learner interest, and enhance 2) participation and 3) recall by instructing sixteen groups of P1 students to prepare Jeopardy! question using poste lectures. Five selected groups were invited self‐select a “leader” and provided pressure‐sensitive buzzers. The remaining groups role‐played “Alex Trebek”, asking questions in a serialized format. Student perception was surveyed to determine whether the activity was 1) helpful, 2) repeatable, 3) important for memorizing content, and, 4) analyzing content for exam‐emphasis.ResultsWe used Qualtrics to build and analyze data collected from our survey. Surprisingly, although 73% of the 57 respondents indicated that exercise was useful, 32% argued for conducting the activity outside of the class time. However, 77% suggested that the activity be repeated. Student showed improvement in performance when some of the game content was used for the final assessment.ImplicationsThis study suggested modification of gaming strategies for use in the pharmaceutical science curriculum, with either a shorter intervention, or one that is implemented in fewer blocks.
The Role of Nrf2 in Primary Human CD4 T Cell Activation and Differentiation
Authors: Turley Alexandra E , Zagorski Joseph , Rockwell Cheryl E 
Published: November 2023

The transcription factor nuclear factor erythroid‐derived 2 like‐2 (Nrf2) responds to cell stress such as reactive oxygen species, electrophilic xenobiotics, and heavy metals. In response to such stress, Nrf2 induces a battery of detoxification, antioxidant, and metabolizing genes. In addition to its cytoprotective functions, Nrf2 has been implicated in immune modulation. Female Nrf2‐null mice develop a disease similar to systemic lupus erythematosus as they age. In addition, Nrf2‐null mice are more sensitive to a number of inflammatory stimuli such as cecal‐ligation and puncture and experimental autoimmune encephalomyelitis, and conversely, Nrf2 activation helps protect against these stimuli. Nrf2 has also been shown to modulate macrophage and dendritic cell function in vitro, and recently our lab has shown that Nrf2 skews CD4 T cell differentiation in primary mouse CD4 cells towards a Th2 phenotype. However, the function of Nrf2 in primary human CD4 T cell activation and differentiation remains unclear. Therefore, the purpose of these studies was to determine the role of Nrf2 in primary human CD4 T cell activation and differentiation. In these studies, peripheral blood mononuclear cells (PBMC) and CD4 cells were isolated from human blood. Cells were treated with either tert‐butylhydroquinone (tBHQ), a commonly used food additive and Nrf2 activator, or 1[2‐Cyano‐3,12‐dioxooleana‐1,9(11)‐dien‐28‐oyl]imidazole (CDDO‐IM), another Nrf2 activator, for 30min, then activated with anti‐CD3/anti‐CD28. Treatment of PBMCs with tBHQ for 6h increased expression of the Nrf2 target genes HMOX, GCLC, and NQO1. Both tBHQ and CDDO‐IM inhibited events of T cell activation at 24h, including production of the cytokines interleukin‐2 and interferon‐γ and expression of the cell surface markers CD25 and CD69. Isolated CD4 T cells show greater inhibition of early events following T cell activation in response to tBHQ as compared to PBMCs. tBHQ treatment increased production of the Th2 cytokines interleukin‐5, interleukin‐4, and interleukin‐13 at 120h by CD4 T cells after activation, and upon restimulation of these cells with anti‐CD3/anti‐CD28, indicating a potential effect on differentiation as well. Overall, these data indicate that Nrf2 inhibits primary human CD4 T cell activation, and potentially shifts differentiation towards a Th2 phenotype.Support or Funding Information(Supported by NIH grants ES018885 and ES007255).
Intracellular upstream signals activate histamine H1 receptor and interleukin‐9 gene expression, sensitive to pollinosis
Authors: Fukui Hiroyuki , Mizuguchi Hiroyuki , Kitamura Yoshiaki , Nemoto Hisao , Kashiwada Yoshiki , Takeda Noriaki 
Published: November 2023

Number of pollinosis patients is increasing worldwidely. It is important for better alleviation to identify the sensitive genes of pollinosis. We observed that stimulation of histamine H1 receptor (H1R) induces H1R up‐regulation through the protein kinase C‐delta (PKC‐delta) activation pathway. Then we hypothesized that H1R up‐regulation worsens the symptoms of pollinosis due to the increase of receptor signaling. Correlation between nasal mucosal H1R mRNA level and symptom score was demonstrated in pollinosis patients, and treatment with antihistamine resulted the normalization of mRNA elevation and alleviation of symptoms. The result suggests that H1R gene functions as a sensitive gene for pollinosis.Elevation of H1R mRNA was induced in nasal mucosa of allergic rhinitis model rats sensitized with toluene 2,4‐diisocyanete. The elevation was completely suppressed with antihistamine treatment. However, alleviation of symptoms was partial, suggesting the existence of the second gene, sensitive to pollinosis. Combination treatment of an antihistamine and Awa‐tea, a fermented tea produced in domestic area of Tokushima, Japan, was attempted. We observed that about 90% of symptom was alleviated. The result suggests that Awa‐tea contains a compound which suppresses gene expression of the second pollinosis sensitive gene.Elevation of interleukin‐9 (IL‐9) mRNA level in nasal mucosa of allergic rhinitis model rats was suppressed with Awa‐tea. IL‐9 mRNA elevation was also observed in RBL‐2H3 cells, a mast cell line, through the activation of calcineurin (CN)/NFAT signaling. The elevation was suppressed with Awa‐tea, however, not with antihistamines.An active compound was attempted to purify from Awa‐tea by monitoring suppressive activity on IL‐9 mRNA elevation, and pyrogallol was identified. Treatment with pyrogallol in combination with epinastine, an antihistamine, markedly alleviated nasal symptoms. Pyrrogallol did not inhibit protein phosphatase activity of CN. Pyrogallol suppressed ionomycin‐induced IL‐9 mRNA upregulation in RBL‐2H3 cells. Treatment with pyrogallol in combination with epinastine markedly alleviated nasal symptoms in allergic rhinitis model rats.Above results suggest that combination therapy will be effective to alleviate allergic rhinitis by suppressing both PKC‐delta and CN/NFAT signaling pathways.
Investigating the Role of Arginine Methylation on Serine Phosphorylation in Histone H3
Authors: Mendiola Aron Judd Perez , Fuentes Daniel , Mendoza Mariel , Zurita‐Lopez Cecilia 
Published: November 2023

We set out to investigate the effects of two PTMs, methylation and phosphorylation, with the goal of understanding the role of arginine methylation on neighboring serine phosphorylation in histone H3. Work by other labs has confirmed that arginine methylation and serine phosphorylation are involved in crosstalk within an AKT motif (RXRXXS/T) where the arginine residue is two residues away from the serine residue. Herein, we use the N‐terminal tail of histone H3 and focus on its arginine‐lysine‐serine (RKS) motif to determine whether a similar interaction is taking place. Serine‐10 hyper phosphorylation of histone H3 is a known biomarker for tumorigenesis, signaling the overexpression of proto‐oncogenes that lead to tumor formation, while arginine‐8 methylation of histone H3 is implicated in gene silencing. Preliminary results have determined that serine‐10 phosphorylation downregulates arginine‐8 methylation in histone H3 peptides. To further analyze the interaction, sequential in vitro methylation and phosphorylation reactions will be carried out using the respective protein arginine methyltransferase (PRMT) and kinase. Of the family of nine known human methyltransferases, emphasis is placed on PRMT1 and PRMT5, which are known to physiologically dimethylate histone H3. While there are several kinases that deposit the phosphate group on serine‐10, we will use mitogen and stress‐activated kinase 1 (MSK1) because it physiologically phosphorylates the serine‐10 residue and specifically targets RKS motif. Methodology for analyzing the methylation and phosphorylation interactions will be done through fluorography, western blot analysis, and thin layer chromatography analysis. Investigating the RKS motif will provide greater insights into protein function and can be a springboard for investigating these modifications in other proteins.Support or Funding InformationNIH Grant #SC2GM118202
Interactive Role of TLR4 and TLR2 in Cardiac Functions During Stressful Conditions
Authors: Bagchi Ashim K. , Akolkar Gauri , Mandal Soma , Ayyappan Prathapan , Yang Xi , Singal Pawan K. 
Published: November 2023

An appropriate balance between anti‐inflammatory interleukin‐10 (IL‐10) and pro‐inflammatory tumor necrosis factor‐α (TNF‐α) cytokines has been suggested for a normal functioning of the heart. It has been suggested that toll‐like receptor 4 (TLR4) promotes IL‐10‐mediated cardiac cell survival while another receptor, TLR2, from the same family is detrimental. We examined the interactive role of these two innate signaling molecules (TLR4 and TLR2) under stressful conditions including interleukin‐10 knockout (IL‐10−/−) mice, global ischemia/reperfusion (I/R) injury rat hearts and shRNA experimental models. Circulating and myocardial levels of TNF‐α as well as apoptosis and fibrosis were higher in IL‐10−/− hearts. Increase in TLR2 in IL‐10−/− hearts indicated its negative regulation by IL‐10. The ex‐vivo I/R also caused a marked upregulation of TLR2 and TNF‐α as well as apoptotic and fibrotic signals. However, 40 min reperfusion with IL‐10 in the I/R hearts, triggered an increase in TLR4 expression. Increase in interleukin‐1 receptor‐associated kinase‐M (IRAK‐M) and IRAK‐2 activity during I/R injury suggested their role in TLR2 signaling. Inhibition of TLR4 activity as a consequence of RNAi‐mediated suppression of myeloid differentiation gene 88 (MyD88) suggested a MyD88‐dependent activation of TLR4. Inclusion of IL‐10 during reperfusion, also significantly downregulated the expression of IRAK‐2, TRAIP and apoptotic signals, caspase 3 and Bax/Bclxl ratio. IL‐10 reduced the TNF‐α receptor‐associated increase in TRAIP/TRADD ‐induced apoptosis during ischemia injury which led to an increase in IL‐1β to mitigate TGF‐βRII‐mediated fibrosis. IL‐10 mitigation of these changes suggests that IL‐10 stimulation through TLR4 signaling, dissociates IRAK‐4 into IRAK‐1 instead of IRAK‐2 and may be an important therapeutic approach in restoring heart health from I/R injury.Support or Funding InformationSupported by Canadian Institutes of Health Research and Research Manitoba.
Na2S, a Fast‐Releasing H2S Donor, Given as Suppository but not Parenteral GYY4137, a Slow‐Releasing H2S Donor, Lowers Blood Pressure in Rats
Authors: Ufnal Marcin , Tomasova Lenka , Drapala Adrian , Koszlewski Dominik , Ostaszewski Ryszard 
Published: November 2023

ObjectivesAlthough several H2S donors are available, their usefulness in research is questionable. Here, we evaluated hemodynamic effects of Na2S, a fast‐releasing H2S donor and GYY4137, a slow‐releasing H2S donor.MethodsHemodynamics were recorded in anesthetized Wistar Kyoto rats (WKY) and Spontaneously hypertensive rats (SHR) at baseline and after: 1) intraperitoneal (i.p.) infusion of either a vehicle (20% DMSO) or GYY4137 or Na2S; 2) intravenous (i.v.) infusion of either the vehicle or GYY4137 or Na2S; 3) per rectal administration of vehicle suppositories or suppositories with Na2S. Stability of GYY4137 in buffers and in rat plasma was evaluated with NMR.ResultsThe vehicle and GYY4137 given i.p. and i.v. did not affect mean arterial blood pressure (MABP), whereas Na2S produced a significant, but transient (2–5 min) decrease in MABP. Administration of Na2S suppositories produced a dose dependent hypotensive response that lasted 60–90 min in WKY and SHR. In the buffers at pH of 7.4 and 5.5 and in rat plasma no reaction of GYY4137 was found during 18 hours of observation. In contrast, rapid decomposition of GYY4137 occurred in buffers at pH 2.0.ConclusionsNa2S given in suppositories exerts a prolonged hypotensive effect in rats. GYY4137 does not affect MABP in rats, which seems to result from its high stability at physiological pH. Suppository formulation of fast‐releasing H2S donors may be useful in basic research as long as a reference slow‐releasing H2S donor is not available.Support or Funding InformationThis study was supported by The National Science Centre, Poland grant No. 2016/22/E/NZ5/00647
Hypoxic Preconditioning Protects Rat Hearts Against Ischemia/Reperfusion Injury via H2S/TRPA1 Pathway
Authors: Ma Ming‐Chieh , Huang Ho‐Shiang , Chen Yih‐Sharng 
Published: November 2023

Hypoxic preconditioning (HPC) protects rat hearts against ischemia/reperfusion (IR) injury. The Ca2+‐permeable transient receptor potential ankyrin 1 (TRPA1) is present in cardiac tissue and plays an important on blood pressure regulation. However, the role of TRPA1 in HPC‐mediated cardioprotection remains unknown. TRPA1 can be activated by a novel gasotransmitter hydrogen sulfide (H2S), which is synthesized endogenously by cystathionine β‐synthase (CBS) and cystathionine γ‐lyase (CSE). Here we examined whether HPC protects the myocardium against IR via the H2S/TRPA1 pathway. Compared to hearts of rats kept in room air, the hearts of rats kept in air preconditioned with 10% oxygen for 4 weeks had better post‐ischemic recovery and less tissue damage when subjected to 30‐min stop of perfusion and 4‐h reflow in a Langendorff apparatus. HC030031, a selective TRPA1 blocker, administered 5 min before reperfusion markedly attenuated the effects of HPC, confirming TRPA1 is a downstream effector in HPC‐mediated cardioprotection. Additionally, HPC markedly increased calcitonin gene‐related peptide (CGRP) and substance P (SP) release in coronary perfusate, which could be reversed by TRPA1 blockade, but not CGRP receptor or SP receptor inhibition. HPC resulted in the upregulation of CBS and CSE, and H2S levels in coronary perfusate, and prevented IR‐induced H2S reduction. Blockade of CBS and CSE by aminooxyacetic acid (AOAA) abrogated the effects of HPC and lowered release of H2S, CGRP, and SP. Mimicking the effects of HPC by given Na2S or NaHS to the AOAA‐treated hearts enhanced cardiac recovery and neuropeptide release during reperfusion. Our results demonstrate that HPC reduces heart susceptibly to IR via the H2S/TRPA1/neuropeptide pathway, as shown by increased enzyme responsible for H2S formation in HPC hearts.Support or Funding InformationThis study was supported by the Ministry of Science and Technology R.O.C. (MOST105‐2314‐B‐030‐009).
Imaging cardiac voltage gated sodium channels using the novel F‐18 radiotracer radiocaine
Authors: Schoenberger Matthias , Hooker Jacob , Strebl Martin , Schroeder Al , McKinsey Timothy , Ambardekar Amrut 
Published: November 2023

Myocardial contraction is controlled by an electro‐mechanical coupling and cardiac action potentials that propagate across the heart. These action potentials are initiated by NaV1.5 voltage gated sodium channels. The role of cardiac NaV1.5 in cardiac disease is reasonably well understood in animal and in vitro models. However, linking changes in NaV1.5 expression levels to human disease in vivo has not yet been possible. “Radiocaine”, an F‐18 radiotracer for positron emission tomography (PET), is the first NaV imaging agent in the heart. Explants from healthy and failing human hearts were compared using radiocaine autoradiography to determine that the failing heart had ~30% lower NaV1.5 levels ‐ the first evidence of changes in cardiac NaV expression in humans as a function of disease. Paving the way for translational imaging, radiocaine proved to exhibit high in vivo specific binding to the myocardium of rats and non‐human primates. We envision that NaV1.5 measurements using PET imaging may serve not only as a powerful research tool, but also as a novel diagnostic to stratify arrhythmia risk and assess for progression of heart failure in patients with a broad spectrum of cardiovascular diseases.Support or Funding InformationMS acknowledges experimental support by PD Dr. Heike Endepols, Dr. Mike Placzek. Work was supported by a MSCA‐IF‐GF grant to MS (INSCAPE 656644) and by the Phyllis and Jerome Lyle Rappaport MGH Research Scholar award (JMH). TAM was supported by the NIH (HL116848, HL127240 and AG043822) and the American Heart Association (16SFRN31400013). AVA is supported by a Scientist Development Grant from the American Heart Association, the Boettcher Foundation's Webb‐Waring Biomedical Research Program, and in part by NIH/NCATS Colorado CTSA Grant Number UL1 TR001082. Contents are the authors' sole responsibility and do not necessarily represent official NIH views. This work was in part supported by access to equipment purchased using NIH shared instrument grants S10RR017208 and S10RR023452.
Effect of All‐Extremity Exercise Training on Left Ventricular Function Assessed by Speckle Tracking Echocardiography in Healthy Older Adults
Authors: Hwang Chueh‐Lung , Petersen John W , Mackay Karen , Yoo Jeung‐Ki , Kim Han‐Kyul , Hwang Moon‐Hyon , Handberg Eileen M , Szady Anita D , Christou Demetra D 
Published: November 2023

Aging is associated with cardiac remodeling and alterations in cardiac function. Recent advances in two‐dimensional echocardiography have allowed for detailed assessment of left ventricular (LV) function using speckle tracking echocardiography (STE). The purpose of this study was to compare the effect of all‐extremity high‐intensity interval training (HIIT) versus moderate intensity continuous training (MICT) on STE‐determined measures of LV systolic and diastolic function in healthy older adults. A total of 50 sedentary older adults (age 65±1.0 years, 17 men) were randomly assigned to HIIT (n=17), MICT (n=17) or non‐exercise controls (CONT, n=16). HIIT (4×4 minutes at 90% of peak heart rate) and isocaloric MICT (70% of peak heart rate) were performed on an all‐extremity non‐weight‐bearing ergometer, 4 times per week, for 8 weeks under supervision. Resting LV global longitudinal strain (S) and strain rate (SR) were measured using two‐dimensional STE of 4‐, 2‐, and 3‐chamber views to assess systolic function (Ssys and SRsys) and diastolic function (early and late SRdia). Thirty‐nine subjects completed the intervention. LV Ssys (HIIT: −19.8±0.9 vs. −20.3±0.9; MICT: −18.2±1.0 vs. −19.7±0.9; CONT: −20.6±0.9 vs. −20.1±0.7), SRsys (HIIT: −1.12±0.06 vs. −1.14±0.05; MICT: −1.06±0.06 vs. −1.20±0.06; CONT: −1.24±0.05 vs. −1.20±0.04), early SRdia (HIIT: 1.13±0.06 vs. 1.19±0.07; MICT: 1.07±0.10 vs. 1.15±0.09; CONT: 1.28±0.07 vs. 1.28±0.10), and late SRdia (HIIT: 0.68±0.06 vs. 0.69±0.05; MICT: 0.56±0.05 vs. 0.71±0.06; CONT: 0.68±0.05 vs. 0.66±0.05) did not change in response to the intervention (P>0.2). In conclusion, STE‐determined LV systolic and diastolic function were unaffected by 8 weeks of all‐extremity exercise training in healthy older adults.Support or Funding InformationThis work was supported by NIH AG 050203 to DDC.