bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive Cardiotoxicity Assessment of COVID-19 Treatments Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Yanagida Shota , Satsuka Ayano , Hayashi Sayo , Ono Atsushi , Kanda Yasunari 
Published: June 2021

Abstract
Coronavirus disease 2019 (COVID-19) continues to spread across the globe, with numerous clinical trials underway seeking to develop and test effective COVID-19 therapies, including remdesivir. Several ongoing studies have reported hydroxychloroquine-induced cardiotoxicity, including development of torsade de pointes (TdP). Meanwhile, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to serve as a tool for assessing drug-induced cardiotoxicity, such as TdP and contraction impairment. However, the cardiotoxicity of COVID-19 treatments has not been fully assessed using hiPSC-CMs. In this study, we focused on drug repurposing with various modes of actions and examined the TdP risk associated with COVID-19 treatments using field potential using multi-electrode array system and motion analysis with hiPSC-CMs. Hydroxychloroquine induced early after depolarization, while remdesivir, favipiravir, camostat, and ivermectin had little effect on field potentials. We then analyzed electromechanical window, which is defined as the difference between field potential and contraction-relaxation durations. Hydroxychloroquine decreased electromechanical window of hiPSC-CMs in a concentration-dependent manner. In contrast, other drugs had little effect. Our data suggest that hydroxychloroquine has proarrhythmic risk and other drugs have low proarrhythmic risk. Thus, hiPSC-CMs represent a useful tool for assessing the comprehensive cardiotoxicity caused by COVID-19 treatments in nonclinical settings.
Inhibition of Mono‐Acyl‐Glycerol Lipase by JZL‐184 Results in Glucolipotoxicity in Pancreatic β‐Cells
Authors: Berdan Charles , Corkey Barbara E , Deeney Jude T 
Published: June 2021

ObjectiveChronic exposure of pancreatic β‐cells to elevated glucose and fatty acid (FA) levels (24–48 hrs) results in glucolipoxity (GLT), a condition mimicking type 2 diabetes with elevated basal secretion and impaired glucose stimulated insulin secretion (GSIS). Acute exposure to mono‐oleoyl‐glycerol (MOG) results in rapid onset (<1hr) of GLT in both clonal β‐cells and dissociated rat islets. Our goal was to determine the effect of altered lipid cycling on β‐cell function using JZL, a mono‐acyl‐glycerol (MAG) lipase inhibitor.MethodsAcute and chronic incubations of clonal β‐cells (INS‐1 832/13) and dissociated rat islets with the MAG lipase inhibitor JZL‐184 were performed. Insulin secretion (HTRF), glycerol release (NADH luciferase) and intracellular lipid accumulation (Nile red) were measured.ResultsJZL (1–10uM) acutely inhibited GSIS and KCl/diazoxide‐stimulated insulin secretion in both dissociated rat islets and INS‐1 cells. Chronic JZL (10uM) exposure in the presence of FA (0.1 mM) increased intracellular lipid droplets and accelerated the development of GLT in INS‐1 cells. Under these same conditions JZL reduced glycerol release indicating MAG lipase was inhibited.ConclusionInhibition of MAG lipase resulted in altered insulin secretion mimicking chronic effects of elevated glucose and FA.Funded by NIH.
Inhibition of secretory Phospholipase A2 Group IIa by thyroid hormone
Authors: Sharma Pragya , Thakran Shalini , Deng Xiong , Elam Marshall B , Park Edwards A 
Published: June 2021

Secretory phospholipase A2 group IIa (PLA2g2a) is involved in multiple biological processes including inflammation and atherosclerosis. In this study, we investigated the regulation of PLA2g2a by thyroid hormone (T3). T3 stimulates expression of genes through the binding of the nuclear T3 receptor (TR) to T3 response elements (TRE). The liganded TRβ recruits transcriptional coactivators to stimulate gene expression. However, as many genes are down regulated by T3 as are stimulated. We found that T3 suppressed the expression of the PLA2g2a gene in hepatocytes, human HepG2 cells and in vivo in rats. To gain insight into the mechanism of transcriptional repression, we cloned the PLA2g2a promoter. We identified a negative TRE (nTRE) in the promoter that bound the T3 receptor as a heterodimer with the retinoid X receptor (RXR). Mutation of the nTRE eliminated the ability of T3 to inhibit PLA2g2a. Knockdown of the nuclear corepressors (NCoR) blocked the T3 inhibition of PLA2g2a. In conclusion our experiments demonstrate a novel inverse recruitment mechanism where liganded TRβ recruits corepressors to inhibit PLA2g2a expression. These results suggest that in addition to the well known role of T3 in regulating genes involved in hepatic metabolism T3 may also modulate the expression of inflammatory genes.This work was supported by National Institute of Health.
Regulation of the ATP Hydrolysis and Transport Cycles of the P‐Glycoprotein Multidrug Transporter by Sterols and Phospholipids
Authors: Sharom Frances J , Clay Adam T , Lu Peihua 
Published: June 2021

Multidrug resistance in many human cancers is linked to expression of the P‐glycoprotein multidrug transporter (Pgp, ABCB1), an ABC protein that exports many structurally diverse compounds from cells. Since Pgp pumps lipophilic substrates out of the membrane, the lipid environment plays an important role in regulating its activity. Using purified Pgp functionally reconstituted into proteoliposomes, we investigated the interaction of Pgp with sterols, and the effect of various defined phospholipids and sterols on basal ATP hydrolysis, Hoechst 33342‐stimulated ATP hydrolysis, and Hoechst 33342 transport. Fluorescence quenching showed that Pgp interacted with the fluorescent sterols, dehydroergosterol (DHE) and NBD‐cholesterol, with high affinity. Cholesterol hemisuccinate (CHS) greatly stabilized the basal ATPase activity of Pgp in detergent and proteoliposomes of some phospholipids, but DHE did not. CHS also had a pronounced effect on thermal unfolding of Pgp, as determined by CD spectroscopy. The stabilizing effects of CHS on drug‐stimulated ATP hydrolysis and drug transport were strongly dependent on bilayer phospholipid composition, and were distinct from those noted for basal ATP hydrolysis. This suggests that the basal ATPase and drug transport cycles of Pgp are distinct, and regulated differently by the lipid environment.Funded by the Canadian Cancer Society (grant #700248).
Novel Signaling Pathways Triggered by a Human Alpha1a‐Adrenoceptor Genetic Variant
Authors: Oganesian Anush , Kleine‐Brueggeney Maren , Gradinaru Irina , Babaeva Ekaterina , Schwinn Debra A 
Published: June 2021

Alpha1‐adrenergic receptors (α1ARs) play an important role in cardiovascular disease. We reported that naturally occurring genetic variant of human α1aAR, with G247R SNP (247R) identified in hypertensive patient, leads to constitutive hyperproliferation of fibroblasts via βarrestin/MMP‐dependent EGFR‐transactivation.Here we examine if the 247R‐triggered hyperproliferation is generalizable in other cell types. Surprisingly, expression of 247R in cardiomyoblasts results in morphological and phenotypical changes to fibroblast‐like cells. RNA and protein expression levels of FSP1, DDR2, MMP2, vimentin, Troponin I, βMHC confirm fibroblast‐like phenotype and cells exhibit agonist‐induced hypertrophy and constitutive, serum‐independent 2–3‐fold increased proliferation. Interestingly, hypertrophy but not proliferation is inhibited by prazosin, an α1aAR‐inverse agonist, suggesting two independent pathways triggered by 247R: proliferation is caused by Gq‐independent, but βarrestin/Src‐dependent EGFR transactivation while hypertrophy is Gq‐dependent.In summary, our data suggest that the naturally occurring human α1aAR genetic variant triggers βarrestin/MMP/ADAM dependent EGFR transactivation pathway leading to hyperproliferation or hypertrophy in different cardiovascular cell types and is a novel hypertension‐associated signaling mechanism.
Apigenin and Kaempferol inhibit LPS‐induced inflammatory responses by regulating intracellular translocation of RNA‐binding protein HuR in macrophages
Authors: Zhang Xiaoxuan , Wang Guangji , Liu Runping , Zhang Luyong , Hylemon Phillip B , Pandak William M , Zhou Huiping 
Published: June 2021

Inflammation is a key player in numerous human diseases including metabolic diseases and cardiovascular diseases. Natural flavonoids are the major components of traditional Chinese medicine and have been used to treat various inflammatory diseases. However, the underlying cellular/molecular mechanisms remain unknown. Apigenin and kaempferol are major, naturally‐occurring plant flavonoids and abundantly present in common fruits and vegetables. The aim of this study was to examine the effect of apigenin and kaempferol on LPS‐induced inflammatory response and further identify the underlying cellular/molecular mechanisms in macrophages.MethodsCultured mouse J774A.1 macrophages and human THP‐1‐derived macrophages were used in this study. The mRNA and protein levels of IL‐1β, IL‐6, TNF‐α, MCP‐1, and COX‐2 were detected by real time RT‐PCR, Western blot and ELISA, respectively. The intracellular distribution of RNA binding protein HuR was determined by Western blot and immunofluorescence staining.ResultsBoth Apigenin and Kaempferol significantly inhibited LPS‐induced expression of proinflammatory cytokines (IL‐1β, IL‐6, TNF‐α, MCP‐1) and COX‐2. LPS‐mediated cytoplasmic translocation of HuR was inhibited by apigenin and Kaempferol.ConclusionApigenin and Kaempferol inhibit LPS‐induced inflammatory responses through regulating intracellular translocation of HuR in macrophages.
FERTILITY ACTIVITY OF AQUEOUS LEAF EXTRACT OF TAPINANTHUS BANGWENSIS ON OVULATION IN FEMALE‐SPRAGUE DAWLEY RATS
Authors: Onadeko Damilola , Nwoke Stella C , Magbagdeola Abiola O , Ebuehi Albert O. , Imaga Ngozi O , Ajayi Godwin O. , Gbotolorun Stella C 
Published: June 2021

The fertility activity of Tapinanthus bangwensis in female rats were investigated in the present study. Twenty four cyclic female rats were administered orally at 1g/kg body weight between 140 and 200g. This was confirmed by checking their vaginal smear for four consecutive cycles.The animals were divided into eight groups of three rats each, group 1 animals served as the control and received equivalent volume of distilled water. Group 2 animals received clomiphene citrate( a fertility enhancing drug), group 3 received duofem(a contraceptive drug), Group 4,5 and 6 received the aqueous leaf extract at 100mg/kg, 200mg/kg and 300mg/kg respectively. group 7 received Vit E and group 8 received Folic acid. They were all administered orally at 9:00am on proestrus to determine it's effect on ovulation. Results revealed a significant difference at P<0.05 between the groups that received the extract at 100mg/kg, 200mg/kg and 300mg/kg. when compared to the control groups. The extract group gave higher mean values of 13.1 as compared to the control of mean value 7.3. Our result gives added scientific support to the use of Tapinanthus bangwensis in the treatment of infertility related problems in women.
Beta synemin binds PKA type I upon beta‐adrenergic stimulation in HL‐1 cells
Authors: Prudner Bethany Cheree , Damron Derek S , Russell Mary A 
Published: June 2021

While our lab previously established that the intermediate filament protein beta synemin is an A‐kinase anchoring protein (AKAP) for PKA type II, which plays a role in maintaining the specificity of the protein kinase A (PKA) signaling pathway; we found that beta synemin also binds PKA type I. Classically PKA type I was thought to be soluble due to low affinity for AKAPs. However, recent work has shown that several AKAPs are capable of binding PKA type I. Here we report yeast two hybrid and FACS‐FRET analyses and co‐immunoprecipitation data that demonstrate the binding of PKA type I to beta synemin. Additionally, this binding is dependent upon stimulation of the beta‐adrenergic (beta‐AR) pathway via isoproterenol. We hypothesize that beta synemin functions as a dual AKAP in which PKA type II is bound during resting conditions then released following beta‐AR stimulation. According to our model, the regulatory subunit of PKA type II is released from beta synemin, leaving the PKA binding site on beta synemin unoccupied and available for PKA type I binding. Though the physiological relevance of the intersection of the two types of PKA at beta synemin remains unclear, due to differences in biochemical characteristics including downstream substrates, the release of PKA type II and binding of type I to beta synemin would allow for a highly coordinated spatial and temporal response to beta‐AR stimulation.NIH R01 HL65701 (DD)
LT1002 Metalloantibody Uses Ca2+ Cofactor
Authors: Ward Aaron D , Yacoub Dina , Erasmus Frank , Huxford Tom 
Published: June 2021

The biologically‐active lipid, Sphingosine‐1‐phosphate (S1P), is a signaling molecule present in cell membranes that promotes heart disease, and tumor growth. Murine, Immunoglobulin G (IgG) LT1002 and human IgG LT1009 specifically bind S1P and inhibit its effects. X‐ray crystallography revealed that two Ca2+ bridge LT1009 and its S1P antigen. This was the first direct structural evidence of metal ion bridging in an antibody: antigen complex. While the role of Ca2+ in the complex is clear, it is unknown to what extent Ca2+ binds in the absence of antigen and whether other biologically significant metals interact with the antibody. To this end, we have conducted quantitative analysis comparing the binding enthalpy, dissociation constant, and stoichiometry of LT1002 and nonmetal‐binding IgG binding to biologically relevant, divalent cations. Isothermal titration calorimetry (ITC) revealed 300uM [LT1002] bound 20mM [Ca2+] with a KD= 238uM with a LT1002:Ca2+ stoichiometry of 1:3. Ba2+, another metal ion that was observed to bind free LT1002 in previous studies, showed no binding to LT1002 by ITC and Ca2+ failed to bind to control murine IgG1. ITC data, in conjunction with the crystal structure of an antigen‐free antibody: Ca2+ complex, indicate that Ca2+ specifically binds to the epitope region of LT1002.Supported by NIH MBRS‐IMSD Grant 5R25GM058906
Compound Seropositivity of neutralizing antibodies against Adipogenic Adenoviruses (ADV36+ and ADV 37+): no additive effect on overweight‐obesity and on Insulin Resistance (IRHOMA). The microbiome across the obesity and into the liver
Authors: Trovato Guglielmo M. , Catalano Daniela , Martines G. Fabio , Trovato Francesca M. , Garozzo Adriana , Pirri Clara , Tonzuso Antonia 
Published: June 2021

A greater hazard of obesity and Insulin Resistance is associated with ADV36 adenovirus seropositivity (ADV36+). Human ADV37 has steatogenic liver effects in humans, but adipogenic effect only in animals: ADV37+patients do not show greater prevalence of obesity vs. ADV37/ADV36 seronegative subjects.Aimto investigate if compound ADV36/ADV37 seropositivity exerts a different effect on overweight‐obesity and IR vs. seronegative subjects and vs. ADV36‐ADV37 single seropositivity. 430 patients were studied, m 157, f 273, age 47.99 ± 15.50 years, BMI 28.14 ± 6.29. Dietary profile was assessed by Adherence to Mediterranean Diet Score (AMDS). Greater BMI (29.74 ± 7.21 vs. 26.47 ± 5.32;p: 0.004) and no difference for HOMA (2.42 ± 1.38 VS 2.28 ± 1.38; p: 0.591) are observed in ADV36+ subjects vs. ADV37+. Compound ADV36+/ADV37+ vs. ADV37+ lone seropositivity has greater BMI: 29.42 ± 6.13 vs. 26.47 ± 5.32; p: 0.001 and greater HOMA: 2.94 ± 2.31 vs. 2.28 ± 1.38; p: 0.029, exactly as the compound seropositivity vs. totally seronegative subjects: BMI: 29.42 ± 6.13 vs. 26.41 ± 5.99; p: 0.0001; HOMA: 2.94 ± 2.31 vs. 2.07 ± 1.39; p: 0.0001; no difference for compound seropositivity ADV36+/ADV37+ vs. ADV36+ lone group. No difference of AMDS was observed between any group.ConclusionADV36+ and ADV37+ compound seropositivity, independently by difference of nutritional profile, has no additive effect for obesity and insulin resistance.
White Potato consumption is positively associated with potassium intake
Authors: Storey Maureen L , Anderson Partricia 
Published: June 2021

Intake of potassium (K), dietary fiber (DF), calcium (Ca), and vitamin D (vit D) are low enough to be of public health concern. White potatoes (WP) contribute DF and are an excellent source of potassium in the U.S. food supply, providing more potassium than most other commonly consumed vegetables. We examined nutrient intakes of children and adults using data from the National Health and Nutrition Examination Survey (NHANES) 2009–2010 and nutrients contributed by WP. Appropriate survey weights were used to calculate average daily intakes of total energy, protein, total fat, saturated fat, monounsaturated fatty acids, polyunsaturated fatty acids, cholesterol, carbohydrates, dietary fiber, vitamin A, vitamin C, thiamin, riboflavin, niacin, vitamin B6, folates, vitamin B12, vitamin K, calcium, phosphorus, magnesium, iron, zinc, copper, sodium, and potassium by males and females 2– 4, 5–8, 9–13, 14–18, 19–30, 31–50, 51–70, and 71+y. Intakes of K, DF, Ca and vit D were all below the RDA or Adequate Intake (AI) levels recommended by the Institute of Medicine. Multivariate regression analyses showed that, controlling for energy intake and demographic variables, WP consumption was positively associated with K intake. Controlling for the other variables in the model, each additional kilocalorie of WP consumed was associated with a 1.6 mg increase in K intake among adults 19+y and a 1.7 mg increase among children and teens 2–18y. These results suggest that children, adolescents and adults do not meet dietary recommendations for key nutrients and consumption of WP increases intake of K.This study was supported by the non‐profit organization Alliance for Potato Research and Education.
Assessment of variation in methods to determine reported iron content of nutrition labels of commercial dark chocolate bars
Authors: Giusti Riana , Kazaks Alexandra 
Published: June 2021

ObjectiveTo assess variation in methods used by industry for determining iron content in dark chocolate bars to provide information for nutrition labeling.MethodsTen brands of dark chocolate bars (70–85% cocoa solids) were purchased from vendors on the US Pacific Coast (San Francisco, California to Victoria, BC). Reported values for iron content (%DV), controlled for serving size, were assessed. Producers were contacted to confirm specific analytical methods or other data utilized for product nutrition labels.ResultsFor the chocolate bars assessed, reported iron content ranged from 4–39 %DV (Mode = 10, SD = 11.7). Label values for iron content were obtained by the following methods: 2 producers used USDA Nutrient Laboratories databases, 4 used analytical testing, 1 was exempt from labeling, 3 did not provide test methods.ConclusionIron, a class II nutrient, is required by FDA to be listed as a percentage of the 18mg daily value (%DV). There is a high level of variability in how dark chocolate producers obtain data for product nutrition labels. This highlights a need for standardized methods to determine iron content for labeling dark chocolate bars. As a result of this analysis, we plan to perform and compare several accepted methods for determining the iron content in dark chocolate bars. Data will be compared to nutrition labels to assess any true variation of iron content in dark chocolate bars.Grant Funding Source: Center for Student Research Bastyr University
Environmental barriers to children's summer outdoor play
Authors: Worobey John , Lelah Lydia , Gaugler Randy 
Published: June 2021

Although the health benefits of physical activity are well documented, it appears that even children may exhibit levels of physical activity that are insufficient to prevent or reduce excess weight gain. In light of the current child obesity epidemic, our objective was to survey children to identify the main reasons they might give for not engaging in outdoor play in the summer, ostensibly a time when school is out and weather is most favorable. For this study, 300 children (age 6–14) were surveyed at four county/4‐H fairs and asked to indicate how important various factors (e.g., heat, traffic, mosquitoes) were in preventing them from playing outside. The reasons ranked highest were bad weather, bullies/gangs, fear of strangers, no street lights, and it being too hot. These results are somewhat consistent with studies that indicate neighborhood safety as a concern (Carver et al., 2008), but add weather conditions as a factor to be considered when seeking to promote outdoor activity. Allowing access to unused school gyms might be a useful strategy for facilitating large motor activity in summer months.This project was supported by a Robert Wood Johnson Foundation Active Living Grant to JW.
Kaempferia galanga L. suppresses melanin synthesis through inhibition of the CREB/MITF in B16 cells
Authors: Jeon Byoung‐Kook , Mun Yeun‐Ja , Woo Won‐Hong , Lee Young‐Eun 
Published: June 2021

Melanin is the main component determining the color of skin and also plays an important role in protecting skin from UV light. Kaempferia galanga Linn. (Zingiberaceae) presents many chemical constituents of the volatile oil extracted from the rhizome. In this study, we examined the effects of the methanolic extract of Kaempferia galanga L. (MKG) on melanogenesis and signaling pathway in B16F10 cells. MKG significantly inhibited ¥á‐melanocyte stimulating hormone (¥á‐MSH)‐induced melanin synthesis and tyrosinase activity, and also decreased ¥á‐MSH‐induced expression of microphthalmia‐associated transcription factor (MITF) and tyrosinase‐related proteins (TRPs). Moreover, MKG reduced the level of phosphorylated cAMP‐response element binding protein (CREB), activity‐regulated transcription factor that functions in melanogenesis. These findings suggest that inhibition of phospho‐CREB and MITF expression may lead to the suppression of melanogenesis in MKG‐treated B16 cells.Grant Funding Source: None
Obesogenic phenotype of offspring of dams fed a high multivitamin diet is prevented by a post‐weaning high multivitamin or high folate diet
Authors: Cho Clara E. , Sanchez‐Hernandez Diana , Reza‐ Lopez Sandra A. , Huot Pedro S.P. , Kim Young‐In , Anderson G. Harvey 
Published: June 2021

High multivitamin (10‐fold, HV) diet fed during pregnancy to Wistar rat dams increases food intake and characteristics of metabolic syndrome in their offspring weaned to the recommended vitamin (RV) AIN‐93G diet. This study determined if a HV or 10‐ fold high folate (HFol) diet fed to the offspring prevents the consequences of the HV gestational diet through epigenetic effects on hypothalamic mechanisms regulating food intake. Male offspring of dams fed the HV diet were weaned to RV, HV or HFol diets for 29 weeks, compared to those born to RV dams and weaned to the RV diet. Food intake, body weight, glucose response to a glucose load, hypothalamic gene expression and global DNA methylation were measured. Both the HV and HFol pup diets prevented the increase in food intake (5%, P=0.03), body weight (8%, P=0.0006) and glucose response (36%, P=0.02) found in offspring of HV dams weaned to the RV diet. Expression of proopiomelanocortin (160%, P=0.004) and brain‐derived neurotrophic factor (BDNF) (170%, P=0.02) was higher in pups fed the HV diet. The HFol pup diet also increased BDNF (130%, P=0.02), and lowered serotonin receptor 2A (60%, P=0.008) expression. Global DNA methylation was similar among groups. In conclusion, increasing the vitamin or folate content of the pup diet is effective in preventing the obesogenic phenotype in offspring of HV dams possibly due to post‐weaning modulation of food intake regulatory mechanisms.Grant Funding Source: Canadian Institutes of Health Research, Institute of Nutrition, Metabolism and Diabetes