bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bypassing Major Venous Occlusion and Duodenal Lesions in Rats, and Therapy with the Stable Gastric Pentadecapeptide BPC 157, L‐NAME and L‐arginine
Authors: Amic Fedor , Drmic Domagoj , Krezic Ivan , Zizek Helena , Peklic Marina , Klicek Robert , Pajtak Alen , Amic Enio , Perisa Marija Milkovic , Tvrdeic Ante , Blagaic Alenka Boban , Seiwerth Sven , Sikiric Predrag 
Published: June 2021

BackgroundUp to now, application of, prototype cytoprotective agent BPC 157 induced bypassing of occlusion, in rats underwent vessels occlusions, through rapid collaterals presentation.AimsTo show that duodenal lesions induced by major venous occlusion can be attenuated by BPC 157, prototype cytoprotective agent, regardless NO system involvement.MethodsIn rats underwent superior anterior pancreaticoduodenal vein (SPDAV)‐ligation, medication was bath at the ligated SAPDV (BPC 157 10 ug, 10 ng/kg/1ml bath/rat; L‐NAME 5 mg/kg/1ml bath/rat; L‐arginine 100 mg/kg/1ml bath/rat, alone and/or together; or BPC 157 10 ug/kg instilled into rat stomach, at 1 min ligation‐time.ResultsUnlike severe course in controls, after BPC 157 application, rats commonly exhibited strong attenuation of mucosal lesion and serosal congestion, improved vessels presentation, much more interconnections, branching raised more than 60% from the initial value; inferior anterior pancreaticoduodenal vein (IAPDV) and superior mesenteric vein (SMV) were both non congested. Interestingly, while at 5 min and 30 min period alone L‐NAME and L‐arginine decreased mucosal and serosal duodenal lesions, their effect was worsening at 24 h period, no effect on the vessels collaterals and branching. Together, L‐NAME+L‐arginine antagonized each other response at any point, and thus, NO‐related effect. With BPC 157 all SAPDV‐ligated rats receiving L‐NAME and/or L‐arginine appear like rats treated with BPC 157 alone.ConclusionsBPC 157, rapidly bypassing occlusion, rescued original duodenal flow through IAPDV to SMV flow, NO‐system related effect.Support or Funding InformationThis work was supported by the Ministry of Science, Education and Sports, Republic of Croatia [grant number 108‐1083570‐3635].This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Development of a TRPA1 Reporter Mouse Model
Authors: Kim Seol‐Hee , Bahia Parmvir , Taylor‐Clark Thomas 
Published: June 2021

Transient Receptor Potential Ankyrin 1 (TRPA1) is an ion channel which is activated by environmental irritants (e.g. formaldehyde and acrolein) and pungent stimuli such as mustard oil, garlic and cinnamaldehyde. TRPA1 is known to be expressed in a subset of nociceptive sensory afferent and thus, playing an important role in defensive reflexes. However, TRPA1 has also been implicated in fibroblast, epithelial cell and smooth muscle cell function, thus it is not entirely clear the extent to which TRPA1 function is restricted to sensory neurobiology.In the current study, we used the Flp‐FRT (flipase‐flipase recognition target) system to generate a TRPA1 reporter mouse model. We generated a TRPA1‐Flp knockin stain which incorporated Flpo after the last endogenous TRPA1 exon. Expression of Flpo was linked to the expression of endogenous TRPA1 via a 2A sequence. The TRPA1‐Flp was crossed with a tdTomato reporter strain carrying frt‐flanked STOP condon (RC::FLTG) to generate a mouse model (Flp::RC) that expresses red fluorescent protein tdTomato in TRPA1 expressing cells. Vagal sensory ganglia were collected from those animals and used for characterization. First, the vagal ganglia were cryosectioned and immunostained to determine nociceptive subtypes using anti‐TRPV1 antibody. Second, primary neurons were isolated from the vagal ganglia and used to monitor calcium influx changes after stimulation with allyl isothiocyanate (AITC), the TRPA1 agonist.tdTomato was expressed in a subset of vagal ganglion neurons, but not in other cell types within the ganglion. The majority of the red fluorescent cells were TRPV1 positive cells and approximately 30% of TRPV1 positive cells co‐expressed TRPA1. In our functional studies, a total of 58 dissociated vagal neurons were assayed and 17 cells expressed tdTomato. Among the tdTomato expressing cells, 11 cells responded to 100 μM AITC. Additionally, 9 cells responded to AITC from 41 of non‐tdtomato expressing cells. Overall, our data suggests that the transgenic mouse model generated using Flp‐FRT system successfully labeled TRPA1 cells. Our preliminary findings suggest that the TRPA1 Flp::RC strain can be utilized in investigations involving TRPA1 ion channel physiology.Support or Funding InformationThis study is funded by National Institutes of Health Common Fund SPARC OT2 (2016–2019): “Functional mapping of peripheral and central circuits for airway protection and breathing”This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Development of Distal Nephron Diuretics Targeting Heteromeric Kir4.1/5.1 Potassium Channels
Authors: Kharade Sujay V. , Kramer Meghan , Denton Jerod S. 
Published: June 2021

Edema is a life‐threatening clinical problem in patients with congestive heart failure (HF) and chronic kidney disease (CKD). Loop diuretics are often prescribed as a first‐line therapy, but the development of loop diuretic resistance can limit the efficacy of these drugs for managing extracellular fluid volume load. A rapidly emerging body of genetic data from rodents and humans has implicated heteromeric inward rectifier potassium (Kir) channels comprised of Kir4.1 (KCNJ10) and Kir5.1 (KCNJ16) as molecular targets for a novel class of diuretics that could potentially be used to circumvent loop diuretic resistance. These channels are prominently expressed on the basolateral membrane of the distal convoluted tubule, where they participate in potassium sensing, regulation of WNK‐SPAK kinase signaling, and sodium reabsorption via the sodium‐chloride co‐transporter, NCC. Homotetrameric Kir4.1 channels are also expressed in the distal nephron; however, they comprise a minor population compared to more prevalent Kir4.1/5.1 heteromeric channels. We recently reported on the discovery of a Kir4.1 channel inhibitor, termed VU0134992, that despite its 10‐fold selectivity for Kir4.1 over Kir4.1/5.1 channels, induces diuresis, natriuresis, and kaliuresis following oral administration in rats (Kharade et al., 2018). This proof‐of‐concept data supports the notion that renal Kir4.1‐containing channels represent “druggable” targets for managing edema in HF and CKD patients. To develop selective inhibitors for probing the therapeutic potential of Kir4.1/5.1 channels, we established a fluorescence‐based, thallium flux assay for interrogating large compound libraries with high‐throughput screening (HTS). The assay was developed using stably transfected Kir4.1/5.1 cell line, is performed in 384‐well plates, and was validated for HTS by meeting a series of rigorous performance benchmarks. In a pilot screen of 6,429 compounds tested at 10 μM, we identified 29 putative inhibitors (0.5% hit rate). We are currently retesting these compounds for activity toward Kir4.1/5.1 and related Kir channels. This work should lead to the development of potent and specific small‐molecule tool compounds for exploring the integrative physiology and therapeutic potential of Kir4.1/5.1 for the treatment of hypertension and edema.Support or Funding InformationFunding NIH R01 DK082884 and 5R21 NS073097‐01S1 to J.S.D.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inhibition of AT2R and BK2R attenuates the effect of high K intake (HK) on thiazide‐sensitive Na‐Cl cotransporter
Authors: Zhang Dandan , Gu Li , Wu Peng , Gao Zhongxizi , Gu Ruimin , Lin Daohong , Wang Wenhui 
Published: June 2021

The basolateral K channel composed of Kir4.1/Kir5.1 in the distal convoluted tubule (DCT) plays a key role in mediating the inhibitory effect of high dietary K (HK) intake on NCC activity by inhibiting the basolateral K conductance and depolarizing DCT membrane potential. Previous studies have demonstrated that the stimulation of type II angiotensin II receptor (AT2R) or bradykinin type II receptor (BK2R) inhibited the basolateral K channels in the DCT. Furthermore, the inhibition of AT2R or BK2R impairs renal K excretion by stimulating the expression of total NCC (tNCC) and phorsphor‐NCC (pNCC). This effect was induced by stimulation of the basolateral K channels because neither PD123319 (AT2R antagonist) nor HOE140 (BK2R antagonist) had a significant effect on NCC in kidney‐specific Kir4.1 knockout mice (Ks‐Kir4.1 KO). The aim of the present study is to test whether the activation of both AT2R and BK2R are required for mediating the effect of HK intake on the basolateral K channels and NCC. Feeding mice (male and female) with HK diet (2% or 10%) for overnight significantly decreased the basolateral K conductance, depolarized the DCT membrane, diminished the expression of pNCC and tNCC and decreased thiazide‐sensitive natriuresis. The deletion of Kir4.1 not only decreases the NCC activity but also abolishes the effect of overnight‐HK diet on NCC. Pretreatment of the mice with PD123319 and HOE140 stimulates the expression of both tNCC and pNCC. Moreover, the overnight HK‐induced stimulation of NCC expression was significantly attenuated in the mice pretreated with PD123319 and HOE140. In contrast, HK diet (overnight) still decreased the expression of both tNCC and pNCC in the mice pretreated with PD123319 alone. We conclude that synergistic activation of AT2R and BK2R is required for the effect of overnight HK diet on NCC activity.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The role of Kv3 channels in regulating epithelial mesenchymal transition
Authors: Sim Hunju , Lee So Yeong 
Published: June 2021

Epithelial mesenchymal transition (EMT) and mesenchymal epithelial transition (MET) are closely related to cancer progression. EMT is demonstrated to alter cell adhesion and cell motility. Recently, it has been suggested that ion channels, including voltage‐gated potassium (Kv) channels are also involved in a consequence of EMT.Dogs are recognized as effective models of cancer development and in clinical therapeutic trials. In the present study, we used canine breast cancer cells, CHMp, which have mesenchymal characteristics, to investigate the involvement of Kv3 channels in the EMT/MET processes. We found that treatment with blood depressing substance II (BDS), which is a specific Kv3 subfamily blocker, increased the expression of cytokeratin‐18, an epithelial cell marker and decreased the expression of vimentin, a mesenchymal cell marker. These results suggest that blockade of Kv3 using BDS induced MET in CHMp cells. Future research is needed to elucidate the specific mechanisms governing the relationship between Kv3 and EMT/MET.Support or Funding InformationThis research was supported by the Bio and Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF‐2016M3A9B6026771).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Long‐Term Dexamethasone Exposure Down‐Regulates Hepatic TFR1 and Reduces Liver Iron Concentration in Rats
Authors: Huifang Li 
Published: June 2021

Exposure to stress is known to cause hepatic iron dysregulation, but the relationship between prolonged stress and liver iron metabolism is not yet fully understood. Thirty 13‐week‐old female Sprague–Dawley rats were randomly divided into two groups, as follows: the control group (saline‐injection) and the dexamethasone group (Dexamethasone (Dex)‐injection 0.1 mg/kg/day). After the 21‐day stress trial, the results showed that chronic Dex administration not only impaired serum corticosterone (p = 0.00) and interleukin‐6 (IL‐6) (p = 0.01) levels, but also decreased white blood cell counts (p = 0.00), and reduced blood lymphocyte counts (p = 0.00). The daily Dex‐injection also significantly reduced body weight (p < 0.01) by inhibiting food intake. Consecutive Dex administration resulted in decreased iron intake (p = 0.00), enhanced serum iron levels (p = 0.01), and increased the serum souble transferrin receptor (sTfR) content (p = 0.00) in rats. Meanwhile, long‐term Dex exposure down‐regulated duodenal cytochrome b (DCYTB) (p = 0.00) and the divalent metal transporter 1 (DMT1) (p = 0.04) protein expression, but up‐regulated ferroportin (FPN) protein expression (p = 0.04). Chronic Dex administration reduced liver iron concentration (p = 0.02) in rats. Hepatic transferrin receptor 1 (TFR1) expression was lowered at the protein level (p = 0.03), yet with uncoupled mRNA abundance in Dex‐treated rats. Enhanced iron‐regulatory protein (IRP)/iron‐responsive element (IRE) binding activity was observed, but did not line up with lowered hepatic TFR1 protein expression. This study indicates that long‐term Dex exposure reduces liver iron content, which is closely associated with down‐regulated hepatic TFR1 protein expression.Support or Funding InformationThis work was supported by grants from the National Natural Science Foundation of China (31302053), the Fundamental Research Funds for the Central Universities (KJQN201404), the Innovation Project of Jiangsu Province Postgraduate Education (2013CXLX13_292), the Priority Academic Program Development of Jiangsu Higher Education Institutions and the Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Epithelial Sodium Channel (ENaC) in Endothelium Modulates Vascular Reactivity with a High Salt Diet
Authors: Mutchler Stephanie M , Kleyman Thomas R 
Published: June 2021

Recent work has shown that ENaC in the endothelium is involved in vascular dysfunction in the setting of high fat diet and increased aldosterone. However, the effects of endothelial ENaC in the setting of high salt diet (HSD) are unclear, especially in mouse models. Therefore, we aimed to investigate the effects of chronic HSD (8 weeks) on vascular health. Using pressure myography, we found that 8 weeks of HSD significantly reduced acetylcholine (Ach) responsiveness in the thoracodorsal artery (TDA) of mice. This dysfunction was ameliorated when 5mM amiloride, an ENaC inhibitor, was added to the lumen of the vessels. In vessels taken from animals fed a control diet (0.4% NaCl), the addition of amiloride had no effect on Ach‐mediated vasodilation. Additionally, amiloride did not significantly alter sodium nitroprusside or phenylephrine response in the 8 week HSD vessels, suggesting amiloride is directly affecting endothelial function, potentially through altered nitric oxide release. Mice fed an 8 week regimen of HSD had significantly higher serum [Na+] and decreased plasma aldosterone level, suggesting that increased aldosterone is not solely responsible for endothelial ENaC expression. Additionally, an endothelial‐specific deletion of gamma ENaC, generated using an inducible cre‐lox system, appears to offer protection from HSD‐induced vascular dysfunction, as three of six control animals showed decreased responsiveness to Ach with 8 weeks of HSD whereas zero of five knockout animals tested showed endothelial dysfunction. Taken together, these data demonstrate that endothelial ENaC has a role in promoting the vascular dysfunction seen with chronic high salt intake. Ongoing studies are examining the role of ENaC in modulating nitric oxide and eNOS phosphorylation status in the endothelial response to a HSD.Support or Funding InformationNIH P30 2P30DK079307‐11, NIH T32 2T32DK061296‐16This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Stimulation of Muscarinic Receptors Activate Acid Sensing Ion Channel 1 in Isolated Mesenteric Artery Endothelial Tubes
Authors: Garcia Selina M , Herbert Lindsay M , Naik Jay S , Resta Thomas C , Jernigan Nikki L 
Published: June 2021

Acid sensing ion channel 1 (ASIC1) belongs to the amiloride‐sensitive degenerin/epithelial sodium channel superfamily and is permeable to both Na+ and Ca2+. ASIC1 is expressed in vascular smooth muscle and/or endothelial cells of various vascular beds and is activated following stimulation of G protein‐coupled receptors (GPCR). In the pulmonary circulation, ASIC1 contributes to GPCR‐induced vasoconstriction and vascular smooth muscle Ca2+ influx via a store‐operated Ca2+ entry (SOCE) mechanism. In small mesenteric arteries, we have recently shown that ASIC1 contributes to acetylcholine (ACh)‐induced vasodilation and endothelial cell Ca2+ entry, however ASIC1‐mediated Ca2+ influx is not SOCE‐dependent in mesenteric artery endothelial cells. Thus, further investigation is needed to understand the mechanism by which ASIC1 is activated by GPCR in small mesenteric artery endothelial cells. Previous studies show ASIC1 is activated by arachidonic acid, therefore we hypothesized that acetylcholine stimulates ASIC1 in mesenteric artery endothelial cells through activation of phospholipase A2 (PLA2) and release of arachidonic acid. To test this hypothesis, we examined endothelial Ca2+ influx via Mn2+ quenching of fura‐2 fluorescence in freshly isolated mesenteric artery endothelial tubes. The PLA inhibitor methyl arachidonyl fluorophosphonate (MAF; 500 nM) attenuated the Ca2+ entry response to ACh, confirming that PLA2‐signaling contributes to the ACh‐induced Ca2+ entry in mesenteric artery endothelial cells. In addition, the selective inhibitor of ASIC1, psalmotoxin 1 (PcTX1; 20 nM), attenuated arachidonic acid‐induced Ca2+‐influx in mesenteric artery endothelial tubes. Although these studies suggest stimulation of muscarinic receptors activate ASIC1 through a PLA2‐arachidonic acid signaling mechanism in mesenteric endothelium, further studies are needed to identify the downstream effector of ASIC1.Support or Funding InformationSupported by National Heart, Lung, and Blood Institute Grants R01 HL‐111084 (to N.L. Jernigan), T32 HL007736 (to T.C. Resta), and American Heart Association Grant 18TPA34110281 (to N.L. Jernigan).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Magnetic resonance hyperpolarisation imaging detects early myocardial dysfunction in a porcine model of right ventricular heart failure
Authors: Agger Peter , Hyldebrandt Janus Adler , Hansen Esben Søvsø Szocska , Omann Camilla , Bøgh Nikolaj , Waziri Farhad , Nielsen Per Mose , Laustsen Christoffer 
Published: June 2021

BackgroundEarly detection of heart failure is important for timely treatment. During development of heart failure adaptive, intracellular processes that evolve prior to macro‐anatomic pathology could provide an early signal of impending heart failure. Therefore, metabolic alterations following cardiac dysfunction would appear early in disease progression. We hypothesised that metabolic imaging with hyperpolarised magnetic resonance can detect early development of heart failure before conventional echocardiography detects cardiac dysfunction.Methods and ResultsFive 8.5 kg piglets were subjected to pulmonary banding and subsequently examined by [1‐13C]pyruvate hyperpolarisation, conventional magnetic resonance imaging, echocardiography, and blood samples every four weeks for 16 weeks. They were compared with a weight matched, healthy control group. Conductance catheter examination at the end of the study showed impaired right ventricular systolic function along with compromised left ventricular diastolic function. After 16 weeks we saw a significant decrease in the left ventricular conversion ratio of pyruvate/bicarbonate from 0.13 (0.04) in controls to 0.07 (0.02) in animals with pulmonary banding, and a significant increase in the lactate/bicarbonate ratio to 3.47 (1.57) versus 1.34 (0.81) in controls. NT‐proBNP was increased by more than 300%, while cardiac index was reduced to 2.8 (0.95) l/min/m2 versus 3.9(0.95)in controls. Echocardiography revealed no changes.ConclusionHyperpolarisation detected a shift towards anaerobic metabolism in early stages of right ventricular dysfunction as evident by an increased lactate/bicarbonate ratio. Dysfunction was confirmed with conductance catheter assessment, but could not be detected by echocardiography. Hyperpolarisation holds a promising future in clinical assessment of heart failure in both acquired and congenital heart disease.Support or Funding InformationThe study is funded by the Danish Children Heart Foundation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Propofol Does Not Attenuate the Cardioprotective Effect of Mild Hypothermia in Swine
Authors: Zimmer Henry , Techiryan George , Smith Cody , Canty John M , Weil Brian R 
Published: June 2021

ObjectivePrevious experimental studies have demonstrated that mild reductions in body temperature can decrease infarct size in the setting of acute myocardial infarction (MI). However, it has been suggested that the cardioprotective effects of mild hypothermia and other conditioning interventions are attenuated by concomitant administration of propofol. To address this issue, we evaluated the relationship between body temperature and infarct size in propofol‐anesthetized swine subjected to prolonged myocardial ischemia and reperfusion.MethodsSwine (n=17) were anesthetized with propofol (10 mg/kg/hour) and subjected to a 60‐minute balloon occlusion of the distal left anterior descending coronary artery (LAD) in the closed‐chest state. Serum cTnI values were quantified by a porcine‐specific ELISA at baseline and 1‐hour after reperfusion. Infarct size (triphenyl tetrazolium chloride) and ischemic area‐at‐risk (AAR; phthalocyanine blue during coronary re‐occlusion) were assessed post‐mortem 3‐hours (n=2), 24 hours (n=5), or 7 days (n=10) after reperfusion.ResultsDirect, statistically significant (p<0.01) correlations were observed between body temperature at reperfusion and infarct size relative to AAR (r=0.75), infarct size relative to LV mass (r=0.70), and serum cTnI 1‐hour after reperfusion (r=0.78). When animals were divided into two groups based on median body temperature at reperfusion (37.5 °C), animals with a body temperature <37.5 °C exhibited significantly smaller infarcts and lower serum cTnI values than animals with a body temperature > 37.5 °C (Table). Importantly, low body temperature‐related reductions in infarct size were observed in the absence of group differences in the duration of reperfusion, LV mass, and ischemic AAR.ConclusionThese results demonstrate that the cardioprotective effect of mild hypothermia is not attenuated in the setting of propofol anesthesia. Furthermore, the marked reduction in infarct size associated with relatively minor diminutions in body temperature provides further support for the notion that even modest reductions in body temperature within a normothermic range may be an effective approach to limit infarct size in patients with acute MI.Support or Funding InformationThe National Heart Lung and Blood Institute (HL‐061610), the American Heart Association (17SDG33660200), the National Center for Advancing Translational Sciences (UL1TR001412), the Department of Veterans Affairs (1IO1BX002659), the New York State Department of Health (NYSTEM CO24351, the UB Center for Undergraduate Research and Creative Activities, and the Albert and Elizabeth Rekate Fund in Cardiovascular Medicine.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.