bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electronic Cigarettes Impair Human Coronary Endothelial Function
Authors: Davoren Katherine , Rashid Mohamad , Nafeh Fida , Moy Norma , Elashoff Robert , Lindner Jonathan , Victor Ronald G. 
Published: June 2021

Electronic (e‐) cigarettes are claimed—but unproven—to be less harmful than standard tobacco cigarettes, which are well known to impair coronary endothelial function and constitute a major cardiovascular risk factor. To determine whether e‐cigarettes cause impairment in human coronary endothelial function, we compared effects of tobacco cigarette smoking and e‐cigarette use to blunt the normal increase in myocardial blood flow (MBF) quantified by contrast enhanced echocardiography perfusion imaging, induced by the exercise pressor reflex (post‐handgrip forearm vascular occlusion). The exercise pressor reflex is a reproducible stimulus to endothelial‐dependent coronary vasodilation while also increasing coronary sympathetic vasoconstrictor drive. The coronary endothelial function testing was performed in healthy young adult cigarette smokers (n=5) and age‐matched e‐cigarette users (n=8), ages 21–38 years: a) after overnight smoking/vaping abstinence; and b) immediately after smoking one Camel‐filtered cigarette or one standard use (15 puffs in 7 minutes) of a popular tank‐style e‐cigarette (Evod: battery 3.7 volts, nicotine content 18 mg). During tobacco abstinence in the young cigarette smokers, the exercise pressor reflex increased mean arterial pressure (MAP) by 21.6 ± 4 mmHg (mean ± SE) and increased MBF by 66 ± 20% over baseline (p<0.05), the latter indicating endothelial‐dependent vasodilation in the human coronary microcirculation. As expected, the MBF failed to increase when the exercise pressor reflex was elicited immediately after cigarette smoking (Δ MBF −2 ± 24%, p=n.s.), indicating acute impairment in coronary endothelial function. The surprising new findings of this study are that MBF also failed to increase and tended to decrease by −45 ± 20% (p=n.s.) when the exercise pressor reflex was elicited immediately after acute e‐cigarette use and by −16 ± 10% (p=n.s.) even when elicited during vaping abstinence (despite comparable mean reflex increases in MAP of 21.1 and 21.6 mm Hg, respectively). Thus, our data to date suggest that, in contrast to what has been widely assumed, e‐cigarette use in young adults causes an impairment in coronary endothelial function that appears to be more persistent than with traditional tobacco cigarettes. Further research is warranted to determine if specific oxidant nanoparticles in e‐cigarette vapor mediate the impaired coronary endothelial function.Support or Funding InformationFunded by Tobacco Related Disease Research Program; ClinicalTrials.gov NCT02612701This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Spironolactone Prevents Elevated Expression of Vascular ENaC in Hypertension
Authors: Mugloo Sama , Ashley Zoe , Leader Catherine , bahn Andrew , Sammut Ivan , Walker Rob , McDonald Fiona , Fronius Martin 
Published: June 2021

Epithelial sodium channel (ENaC) in the kidneys plays an important role in maintaining salt/water homeostasis and blood pressure. Recent research has demonstrated expression of ENaC in the vasculature, and a new role in regulation of the vascular tone. An increase in vascular tone is seen in vascular diseases such as hypertension indicating that changes in ENaC expression in the vasculature may contribute to hypertension. In this study, we hypothesized ENaC expression in arteries will increase in hypertension and that the treatment with antihypertensive drug, spironolactone (spiro‐) will reduce ENaC expression in arteries.Conduit (aorta) and resistance (mesenteric) arteries from male transgenic rats (Cyp1a1‐ren2) with diet‐inducible hypertension (0.167% indole‐3‐carbinol) were isolated and a‐, b‐ and g‐ENaC expression was analyzed by qRT‐PCR. Arteries from four animal groups were analyzed: (1) normotensive (2) hypertensive, (3) normotensive spiro‐ and (4) hypertensive spiro. Rats were fed a control or hypertensive diet for 6 weeks and in two groups (3 & 4) spiro‐ (4.41mg/kg/day) was introduced 2 weeks after the start of the diet.In mesenteric arteries of hypertensive animals a significant increase in both a‐ENaC (p=0.02) and g‐ENaC mRNA level (p=0.04) was observed in comparison to normotensive arteries. In aortas, there was a significant increase in a‐ENaC mRNA level (p=0.006) in hypertension but no change in b‐ and g‐ENaC expression. In mesenteric arteries, spiro‐treatment decreased a‐ENaC and g‐ENaC in comparison to hypertensive controls. In aortas, a‐ENaC mRNA level was significantly decreased (p=0.002) by spiro‐treatment compared to hypertensive controls.In summary, we observed an upregulation of vascular ENaC mRNA in arteries during hypertension and found that antihypertensive treatment with spironolactone decreased this upregulation. This data suggests a strong link between pathogenesis of hypertension and vascular ENaC expression.Support or Funding InformationUniversity of Otago Doctoral Scholarship, Department of Physiology, Otago Medical Research Foundation, Lottery Grants BoardThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Preeclampsia alters the role of nitric oxide in androgen metabolite‐induced vasorelaxation of rat uterine artery
Authors: Hanson Andrea E. , McKenna Joshua M. , Garcia Nikolas W. , Perusquia Mercedes , Stallone John N. 
Published: June 2021

Preeclampsia (PE) is a pregnancy‐induced disorder and a major cause of both fetal and maternal morbidity and mortality. During pregnancy, the placenta produces abundant androgens, and these rapid, non‐genomic vasodilators may serve to maintain uterine blood flow during normal pregnancy and may be impaired in PE. Of the known placental androgens, testosterone (TES) and its genomically inactive metabolite, 5β‐dihydrotestosterone (5β‐DHT), were previously reported to induce vasorelaxation in uterine arteries (UA). This study aimed to determine the nitric oxide (NO) signaling mechanisms involved in TES‐ and 5β‐DHT‐ induced relaxation in the rat UA using the DOCA‐salt model of PE. Endothelium‐intact UA rings (200 μm, dia.) from normal pregnant (NP) and DOCA‐treated pregnant (DSP) female (F) Sprague‐Dawley rats (250–300g) were prepared for measurements of isometric contractile force (DMT myograph). UA were pretreated with L‐NG ‐monomethyl arginine citrate (L‐NMMA, 100 μM), a non‐selective nitric oxide synthase (NOS) inhibitor or NW‐propyl‐L‐arginine (200 nM), a specific nNOS inhibitor. UA were then precontracted with U‐46619 (thromboxane A2 agonist, 1 μM) and a concentration‐dependent relaxation to TES and 5β‐DHT was obtained (0.1–1000 nM). Data are means ± SE (n = 6 rats). Androgen‐induced maximal UA relaxation was reduced by L‐NMMA in NP (TES: 33.84 ± 4.6 vs. 1.24 ± 4.0 and 5β‐DHT: 28.12 ± 6.1 vs. 2.0 ± 6.3) and in DSP (TES: 36.23 ± 4.6 vs. 4.44 ± 2.3 and 5β‐DHT: 30.71 ± 4.6 vs. 0.9 ± 2.4). Maximal relaxation was reduced by NW‐propyl‐L‐arginine in NP for both TES (24.53 ± 6.1) and 5β‐DHT (20.38 ± 3.8) and in DSP for 5β‐DHT (18.78 ± 6.7); however TES induced UA relaxation was unchanged with NW‐propyl‐L‐arginine in DSP (33.60 ± 10.4). These data suggest that: 1) androgen‐induced UA relaxation is both nNOS and eNOS dependent in NP; and 2) nNOS dependent TES‐induced relaxation of UA is decreased in DSP. (State of Texas)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of H1/H2 histamine receptor blockade on mitochondrial function in rodent brain following prolonged exercise
Authors: Wallace Helen E. , Davidson Laura R. , Bell Mackenzie CW. , Brebner Karen , Kane Daniel A. 
Published: June 2021

Exercise has been shown to stimulate histamine release, which mediates vasodilation in exercising tissue and is sustained post‐exercise. Blockade of H1 and H2 receptors with antihistamine drugs attenuates this effect in skeletal muscle. Research examining the effects of exercise‐related histamine action on cellular level processes is relatively sparse. There also remains limited understanding of the impacts of histamine receptor blockade on non‐exercising tissue, such as the brain. To this end, 36 adult male Wistar rats (75–94 days old, 441.2 ± 39.5 g body wt) were randomly assigned to three groups: (1) given H1 and H2 receptor antagonists fexofenadine (7.11 mg/kg) and ranitidine (3.95 mg/kg) via oral gavage 1 hr prior to treadmill exercise (1 hr, 20 cm/s); (2) completed the exercise without drug, and (3) control. All groups received body mass‐proportional oral gavage volumes (water or antihistamines). One hour post‐exercise, mitochondrial function was assessed in saponin‐permeabilized prefrontal cortex and dorsal hippocampus brain sub‐regions. There was no effect of exercise or drug treatment on mitochondrial substrate‐dependent oxygen consumption (JO2; high‐resolution respirometry), or in mitochondrial hydrogen peroxide emission (mH2O2; fluorometric monitoring of Amplex Red oxidation) in permeabilized prefrontal cortex or the dorsal hippocampus. These results suggest negligible effects of oral H1/H2 antagonists on mitochondrial metabolism in brain following exercise. This supports prior evidence suggesting the effects of H1/H2 inhibition remain localized in exercising muscle. Other studies report systemic increases in histamine levels following exercise, however, which suggests further research may reveal a relationship between histamine receptor blockade and cellular processes in non‐exercising tissues.Support or Funding InformationThe Natural Sciences and Engineering Research Council of Canada (NSERC), The Nova Scotia Health Research Foundation (NSHRF), and Canada Foundation for Innovation (CFI)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The TLQP‐21 neuropeptide and the complement 3a receptor (C3aR1) regulate a novel prolipolytic pathway
Authors: Sahu Bhavani Shankar , Cero Cheryl , Han Ruijun , Razzoli Maria , Grady Scott O. , Bartolomucci Alessandro 
Published: June 2021

Obesity results in fat mass accumulation and is associated with serious comorbidities such as type 2 diabetes and cardiovascular disease. Targeting excess fat by lipolysis has been a major challenge due to side effects. TLQP‐21, a neuropeptide encoded by the pro‐peptide VGF (nonacronymic), that binds the complement 3a receptor 1 (C3aR1) on the adipocyte membrane, is emerging as a novel modulator of adipocyte functions and a potential target for obesity. However, the molecular mechanism is still largely uncharacterized. In current study, we aim to understand the role of C3aR1 in murine, human adipocytes and in vivo in diet‐induced obese mice. In vitro experiments using loss and gain of function approaches in 3T3‐L1 adipocytes demonstrate that C3aR1 knockdown prevents TLQP‐21‐induced prolipolytic response. Likewise, TLQP‐21 treatment decreases body weight and fat mass in diet induced obese mice by a mechanism requiring C3aR1 activation. Finally, we demonstrate that this lipolytic pathway is conserved in human adipocytes and can be activated by the rodent but not the human TLQP‐21 peptide, a finding in line with our previous demonstration of a low potency of the human compared to the rodent TLQP‐21 at the human C3aR1 (Cero et al., Structure 2014). In summary, our results identified a novel lipolytic pathway involving TLQP‐21 and C3aR1, a receptor classically studied for its role in innate immunity thus offering a novel target to develop new effective pharmacotherapies for obesity and associated diseases.Support or Funding InformationNIH grant (NIH/NIDDK R01DK102496)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A feedback control of insulin signaling by transcription factor HMG box‐containing protein 1 (HBP1) in adipocytes
Authors: Chen Zih‐Hua , Chan Chien‐Yi , Lee Ming‐Fen , Huang Chun‐Yin 
Published: June 2021

Adipocytes are sensitive to insulin control of cellular glucose utilization, thereby facilitating the maintenance of blood glucose concentration. Previously we demonstrated that transcription factor HBP1 is highly expressed in differentiated adipocytes, which, together with CCAAT/enhancer‐binding proteins C/EBPβ and C/EBPα, regulates adipocyte differentiation. To further gain insight into the biological role of HBP1 in mature adipocytes, here, we employed mouse embryonic fibroblast (MEF)‐derived adipocytes to test the hypothesis that HBP1 might regulate insulin sensitivity in adipocytes. First, suppression of HBP1 by siRNA‐mediated gene silencing significantly attenuated glucose uptake as shown by 2‐NBDG glucose uptake assay. We then examined the insulin‐signaling pathway to unravel the molecular mechanism by which HBP1 commands adipocytes to take up glucose. Under serum starvation, the transcription of insulin receptor (InR) was increased, whereas HBP1 silencing down‐regulated the expression of InR in adipocytes, indicating that HBP1 is able to promote insulin sensitivity under insulin insufficient state. However, the addition of insulin (2 nM for 6 h) led to a significant decrease in the transcription of HBP1, InR, and IRS1/2 (insulin receptor substrate 1/2). Moreover, HBP1 siRNA led to increased level of p‐S307 IRS‐1 that is associated with blockade of the insulin signaling, and also resulted in an unexpected induction of glucose transporter 4 (GLUT4). The upregulation of GLUT4 may function as a compensation mechanism for the defective insulin signaling caused by HBP1 silencing. Taken as a whole, our results reveal a key feedback control mechanism for HBP1 in regulating insulin signaling and glucose metabolism.Support or Funding InformationThis work was supported by the grant to MOST 105‐2320‐B‐039‐044‐MY2 C‐Y Huang.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Distinct Effect of Invasive and Non‐invasive Breast Cancer Cells on Vasculogenic Capacity of Endothelial Progenitors
Authors: Lee Hyunsook , Shah Sajita , Kim Eun‐Sook , Moon Aree , Kang Kyu‐Tae 
Published: June 2021

Blood vessel formation plays an essential role in tumor growth and metastasis. Cancer cells secrete various pro‐angiogenic factors that activate preexisting vascular endothelial cells as well as induce recruitment of bone‐marrow‐derived endothelial progenitors; endothelial colony forming cells (ECFC). The interactions between cancer cells and endothelial cells have been largely investigated, but it has been rarely studied whether the vasculogenic capacity of ECFC are differently affected by invasive and non‐invasive phenotype of the cancer cells. Thus, we investigated to determine the vasculogenic potentials of invasive and non‐invasive breast cancer cells. MDA‐MB‐231 and MCF7 were applied as invasive and non‐invasive breast cancer cells. Bone marrow‐derived ECFC were isolated from human peripheral blood. Tubular structure number and length as well as spheroid sprout number and length formed by ECFC was increased when treated with MDA‐MB‐231‐derived conditioned medium (CM) compared with MCF7‐derived CM. Migration of ECFC was also increased by treatment of MDA‐MB‐231‐derived CM compared to MCF7. To mimic tumor microenvironment, ECFC were directly co‐cultured with cancer cells. Tube formation of ECFC was enhanced under the co‐culture condition with MDA‐MB‐231 compared to ECFC alone control. Interestingly, ECFC co‐cultured with MCF7 significantly decreased tube formation. Our results suggest that MDA‐MB‐231 and MCF7 promote ECFC vasculogenesis in different manners, which may be the important determinants to characterize invasive and non‐invasive phenotype of the cancer cells.Support or Funding InformationThis research was supported by Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2016r1a6a1a03007648), and supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2017R1A2B4005463).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Blockade of 20‐HETE synthesis confers resistance to stress‐induced apoptosis in renal tubular cells
Authors: Alexander Larry D. 
Published: June 2021

Changes of the levels of 20‐Hydroxyeicosatetraenoic acid (20‐HETE), an ω‐hydroxylation product of arachidonic acid catalyzed by cytochrome P450 4A, have been recently reported to mediate program‐cell death associated with renal ischemia‐reperfusion (IR) injury. In this study, we evaluated the effects of 20‐HETE and a 20‐HETE synthesis inhibitor N‐hydroxy‐N′‐(4‐butyl‐2 methylphenyl) formamidine (HET0016), on stretch‐mediated cell death in renal epithelial (HK‐2) cells. Stretch‐induced apoptosis was detected by measuring histone‐associated DNA fragments using ELISA (Enzyme‐Linked Immunosorbent Assay) and caspase activity assays. A 20‐HETE competitive in vitro ELISA kit was used for the determination of 20‐HETE levels in biological samples. 20‐HETE protein levels were analyzed using Western blot. Here we report that HK‐2 cells express cytochrome P450 (CYP) 4A protein and produce 20‐HETE when stimulated with cyclic stretch. Exogenous application of 20‐HETE increased, whereas inhibition of 20‐HETE production with HET0016 attenuated 20‐HETE‐ and cyclic stretch‐induced apoptosis. Our results also show that 20‐HETE and cyclic stretch causes time‐dependent activation of c‐Jun N‐terminal kinase (JNK) activity, which was significantly attenuated by HET0016. In addition, the JNK inhibitor SP600125 significantly attenuated cyclic stretch‐and 20‐HETE‐induced apoptosis, whereas the extracellular signal‐regulated kinase1/2 (ERK1/2) and p38MAPK inhibitors PD98590 and SB23580, respectively, were without affect. These data provide the first evidence that 20‐HETE is a potent and direct inducer of apoptosis in renal proximal tubule cells. More importantly, these observations demonstrate a critical upstream role of JNK in cyclic stretch‐induced apoptosis dependent of ω‐hydroxylation of arachidonic acid.Support or Funding InformationThis work was supported by a Scholarly Activity and Research Program (SARP) grant to Dr. Larry D. AlexanderThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Insulin receptor‐related receptor as an extracellular pH sensor regulating bicarbonate excretion
Authors: Petrenko Alexander George , Mozhaev Andrey , Serova Oxana , Deyev Igor 
Published: June 2021

The acid‐base balance in the organism at the system level is controlled primarily by the kidneys and lungs. In the kidneys, this function is performed by the intercalated cells of two types; alpha cells excrete excess acids while beta cells excrete excess bases as bicarbonate. In a result of the biochemical analysis of the insulin receptor‐related receptor (IRR), a receptor‐like tyrosine kinase enriched in beta‐intercalated cells, we discovered its ability to activate upon the extracellular treatment with mildly alkaline media. IRR is a close homolog of the receptors of insulin and insiln‐like growth factor but cannot be activated by to their agonists whereas IRR homologs do not respond to extracellular pH changes. This pH‐sensing property of IRR is evutionary conserved from amphibians to mammals. The IRR activation by alkali resembles a typical ligand‐receptor interaction since it is dose‐dependent and saturable, specific in relation to other homologous receptors, defined by the structure of the IRR ectodomain and accompanied by its conformational changes. Mutagenesis revealed two sites in the IRR ectodomain that act synergystically to induce the receptor activation. IRR activation triggers intracellular signaling resembling the insulin receptor pathway. We obtained a panel of monoclonal antibodies against the IRR ectodomain, one of them being able to activate the receptor, and another – to inhibit its response to alkaline media. Altogether, the obtained data suggest that IRR is a cellular pH sensor. We used kcnockout mice to address IRR systemic functions. The knockout mice are viable in normal conditions but fail to excrete excees bicarbonate upon experimentally induced alkalosis. Nevertheless, the increased blood bicarbonate is compensated by CO2 retention that keeps the blood pH within the physiological range. We performed comparative analyses of knockout and wild type mice kidney and brain transcriptomes and identified statistically valid changes in the expression of several proteins, in particular, ion transporters. Also, a behavioral phenotype of the knockout mice was revealed. They appeared to be less socially active and less agressive as compared to their wild‐type littermates.Support or Funding InformationThis work was financially supported by the Russian Science Foundation (grant № 14‐50‐00131)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
P2Y receptor regulation of apical K2P channels involved in K secretion by human mammary epithelial cells
Authors: Srisomboon Yotesawee , Zaidman Nathan A. , Maniak Peter J. , Deachapunya Chatsri , O'Grady Scott M. 
Published: June 2021

In this study, the molecular identity and regulation of ion channels involved in K+ secretion by human mammary epithelial cells was investigated. Voltage clamp experiments were performed on human mammary epithelial monolayers basolaterally treated with the pore‐forming antibiotic amphotericin B dissolved in a solution with intracellular ionic composition. Addition of benzamil to the apical solution inhibited the basal current, consistent with inhibition of sodium absorption. Moreover, apical addition of the K2P channel blockers quinidine, bupivacaine and a selective TASK1/TASK3 inhibitor (PK‐THPP) all produced concentration‐dependent increases in apical membrane current resulting from inhibition of apical K+ efflux. Expression of mRNA for nine K2P channel subtypes was demonstrated by qRT‐PCR. Western blots using biotinylated apical membranes and confocal immunocytochemistry showed that TWIK1, TREK1, TREK2, TASK1 and TASK3 were all located in the apical membrane. Purinergic receptor stimulation with apical UTP also increased apical membrane current, however pretreatment with GF109203X, a pan‐selective inhibitor of PKC, inhibited the effect of UTP. Furthermore, PKC activation with phorbol 12‐myristate 13‐acetate, like UTP, also increased the current. We conclude that basal K+ secretion depends on the activity of multiple K2P channel subtypes, some of which are inhibited by purinergic receptor stimulation and activation of PKC.Support or Funding InformationThis study supported by a Royal Golden Jubilee PhD program Fellowship from The Thailand Research Fund (PHD/0204/2551) to YS and CD and by the NIH (R01 AI128729‐01) to SMO.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.