bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery and characterization of a novel class of phenylsulfonylpiperazine containing compounds as inhibitors of the Aedes aegypti Kir1 (AeKir1) potassium channel
Authors: Mccarthey James Bryson , Aretz Christopher D , Morwitzer Melody D , Sanford Austin G , Hogan Alicia M , Portillo Madeline V , Kharade Sujay V , Kramer Meghan , Rusconi Renata , Piermarini Peter M , Denton Jerod S , Hopkins Corey R 
Published: June 2021

Vector‐borne diseases such as Zika virus, dengue fever and chikungunya virus are transmitted by infected Aedes aegypti female mosquitoes and affect a large portion of the world's population. The use of neurotoxic insecticides to reduce mosquito populations has led to the emergence of genetically resistant strains of mosquitoes over the last several decades, prompting us to explore other physiological targets that might be suitable for insecticide development. Inward rectifier potassium (Kir) channels play essential roles in the physiology of the mosquito Malpighian (renal) tubule and represent “druggable” targets that can be exploited to inhibit renal excretory function. We have previously reported on the discovery of various scaffolds that are active against the Aedes aegypti Kir1 (AeKir1) channel. Herein we report the synthesis and biological characterization of a new 2‐nitro‐5‐(4‐(phenylsulfonyl) piperazin‐1‐yl)‐N‐(pyridin‐4‐ylmethyl)anilines scaffold as an inhibitor of the AeKir1 channel. This new scaffold is more potent in vitro compared to the previously reported scaffolds, in addition, the molecules kill mosquito larvae.Support or Funding InformationThis work is funded by National Institutes of Health grant 1R21 AI128418‐01A1.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Increased vasopressin secretion during preeclampsia despite normal plasma osmolality
Authors: Zhang Shao Yang , Ray Alyssa T , Lewis Emma , Deng Guorui , Sandgren Jeremy A , Scroggins Sabrina M , Xue Jiarui , Pearson Nicole A , Zepeda‐Orozco Diana , Sigmund Curt D , Santillan Mark K , Pierce Gary L , Santillan Donna A , Grobe Justin L 
Published: June 2021

Preeclampsia (PE) is a cardiovascular disorder that affects 4–7% of pregnancies and typically involves new onset hypertension, proteinuria, and edema. Diagnosis of the disorder is formally performed in the second half of gestation based upon clinical signs, but we and others have discovered that maternal plasma levels of copeptin (CPP, the stable C‐terminal fragment of arginine vasopressin, AVP) are elevated already in the first trimester and are highly predictive of the development of PE. Further, chronic low‐dose AVP infusion is sufficient to model almost all the clinical features of PE in pregnant mice. Our objective is therefore to understand the cause of elevated AVP secretion in human PE. Previous studies indicate that blood volume is reduced during PE, but no change in osmolality has been noted. We therefore hypothesized (i) that plasma AVP levels are elevated in early gestation of pregnancies that later develop PE, and (ii) that elevated AVP and CPP secretion during PE is secondary to altered volume regulation. Blood samples (1st and 2nd trimester) from women who later developed PE or represent clinically‐matched case controls were obtained from the Maternal Fetal Tissue Bank (IRB#200910784) at the University of Iowa. Consistent with our first hypothesis, plasma levels of AVP, assessed by ELISA after Sep‐Pak C18 reversed solid phase extraction, were increased in 1st and 2nd trimester from women who later developed PE (25.5±3.6, n=63 vs 52.1±22.2, n=5 pg/mL, mean±SEM, p=0.01) despite no change in osmolality (279.6±0.7, n=46 vs 277.5±1.2, n=4 mOsm/kg H2O). Plasma sodium was increased in 1st and 2nd trimesters before the onset of PE (133.9±0.6, n=91 vs 138.5±0.6, n=6 mmol/L, p<0.05), but potassium was unchanged (4.13±0.05 vs 4.38±0.14 mmol/L). These findings support the conclusions that (i) AVP levels are indeed increased in early pregnancy before the onset of clinical symptoms of PE, as was suspected based upon previous studies of CPP; that (ii) the defended osmolality set‐point is similar between control and PE pregnancies, and therefore chronically elevated osmolality is unlikely to be the major cause of elevated AVP secretion during PE, and that (iii) offsetting changes in concentrations of individual osmolytes may be present during PE.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Luteolin protects human glomerular endothelial cells from TNF‐α‐induced endothelial dysfunction by attenuating ET‐1 and ROS production
Authors: Yang Weiwei , Bradshaw Jessica , Bakrania Bhavisha , Duncan Jeremy , Satchell Simon , Spradley Frank , Granger Joey , Rana Sarosh 
Published: June 2021

Preeclampsia (PE) is a pregnancy‐specific syndrome that affects 5~8% pregnancies and is a leading causes of maternal and neonatal morbidity and mortality, especially in low‐income and middle‐income countries. Although the underlying mechanism remains unclear, PE is associated with maternal endothelial dysfunction characterized by elevated endothelin (ET‐1) and reactive oxygen species (ROS). Tumor necrosis factor‐α (TNF‐α) has been reported as one of the regulators of endothelial dysfunction and this inflammatory factor is elevated significantly in the placenta of patients with PE. Recently, luteolin has drawn wide scientific attention due to a number of health benefits and reduced risk of several diseases, including hypertension and cardiovascular disease. However, whether luteolin might have therapeutic potential in PE is unknown. We tested the hypothesis that luteolin protects endothelial cells against TNF‐α by reducing ET‐1 and ROS production. We pretreated immortalized human glomerular endothelial cells (hGEnCs) with luteolin for 1 hour before recombinant human TNF‐α exposure. We found that exposure of hGEnCs to TNF‐α for 24 h significantly increased the release of ET‐1 by 1.9 fold (3.10±0.70 pg/mL vs 1.07±0.20 pg/mL, p<0.05). Pretreatment with luteolin significantly attenuated TNF‐α‐induced ET‐1 release in a dose‐dependent manner, in particular, 20μM luteolin completely attenuated the effect of TNF‐α on ET‐1 production (3.10±0.70 pg/mL vs 0.56±0.08 pg/mL, p<0.01). We further utilized 2',7'‐dichlorodihydrofluorescein diacetate (H2DCFDA) assay to assess whether luteolin has the potential to prevent TNF‐α‐induced ROS in hGEnCs. We found that luteolin significantly ameliorated the effect of TNF‐α on ROS generation. Pretreatment with luteolin at physiologically relevant concentrations (2 μM) significantly decreased TNF‐α‐induced ROS production within cells (fluorescent intensity: 1795±89.26 vs 1237±98.29, p<0.01), while at 20μM luteolin, TNF‐α‐induced ROS was markedly inhibited by 66% (fluorescent intensity: 1795±89.26 vs 618.5±40.81, p<0.01). Taken together, our preliminary data suggest that luteolin significantly attenuates TNF‐α‐induced ET‐1 release and ROS generation.Support or Funding Information81601318, P01HL051971, P20GM104357, T32HL105324, 18POST33990293, HL130577This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Renal Medullary Histone Deacetylase Dependent Regulation of Fluid‐Electrolyte Homeostasis During High Salt Feeding
Authors: Hyndman Kelly A , Speed Joshua S , El‐Dahr Samir , Olson Eric , Pollock David M , Pollock Jennifer S 
Published: June 2021

Histone deacetylase enzymes (HDACs) regulate gene transcription through epigenetic modification of chromatin structure. HDAC inhibitors (HDACi) are being examined as anti‐inflammatory and anti‐fibrotic therapies in cardiovascular disease. However, adverse events of HDACi use include hyponatremia, hypokalemia, and hypertension suggesting that HDACs are involved in regulation of fluid‐electrolyte balance. Thus, we sought to define the renal physiology and pathophysiology role of HDACs to understand mechanisms of these potentially fatal side effects. We found that class I HDACs are expressed in the human and rat kidney, and that inner medullary HDAC1 abundance is increased 4‐fold with high salt feeding in normotensive male rats. During high salt loading, inhibition of renal medullary class I HDACs with chronic intramedullary interstitial infusion of MS275 (1 mg/kg/day) resulted in a significant increase in polyuria (vehicle = 34.4 ±2.0 ml/day, MS275 = 49.8 ±5.0 ml/day, n = 5, P = 0.012) and decreased plasma potassium (vehicle = 4.9 ±0.2 mmol/L, MS275 = 3.9 ±0.13 mmol/L, n = 5, P = 0.0046). Furthermore, HDACi led to changes in the homeostatic mechanisms of fluid‐electrolyte balance including renal nitric oxide deficiency (vehicle = 9.6±2.7 mmol NOx/day, MS275 = 3.1±0.66 mmol NOX/day, n = 5, P = 0.033). We generated doxycycline‐inducible, collecting duct specific, HDAC1 and HDAC2 knockout mouse (iCDHDAC12KO). In male iCDHDAC12KO mice on a high salt diet, there was significant polyuria (control = 12.9±1.8 ml/day, KO 26.1±5.6 ml/day, n=4–5, P =0.04) and reduced urinary NOX(control = 0.9±0.2 mmol/day, KO = 0.3±.06 mmol/day, n=4–5, P = 0.04). Our findings point to a mechanism whereby HDAC1 promotes NO synthase expression through epigenetic regulation of chromatin structure at the Nos1and Nos3promoters. Given the promising research of HDACi to treat cardiovascular disease, this study provides insight on the mechanisms of the adverse events, which may be fatal to critically ill patients.Support or Funding InformationNIH NIDDK K01DK105038 and the UAB Pittman Scholarship to KAH, NHLBI HL127178 to JSS, and P01 HL123267 to DMP and JSP.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Lysine Specific Demethylase‐1 Deficiency Accelerates the Development of Hypertension and Renal Damage During Long Term Sodium Intake
Authors: Katayama Isis Akemi , Cullinane Danielle L , Williams Gordon H , Heimann Joel Claudio , Pojoga Luminita H 
Published: June 2021

AimsThis study aimed (1) to evaluate the timing of onset for changes in cardiovascular and renal (CVR) health during long term sodium loading in Lysine Specific Demethylase 1 (LSD1) deficiency and (2) to assess whether salt restriction can prevent these effects.MethodsLSD1‐HET and WT mice were randomized to high salt (HS), moderate salt (NS) or low salt (LS) and followed longitudinally for 12 months. BP, albumin/creatinine ratios (A/C), plasma aldosterone (PA) and renin activity (PRA) were assess monthly. At the end of study the renal arterial resistance index was measure by Doppler ultrasound.ResultsThe SBP (mmHg) increased progressively during the study, and reached significance on the 5thmonth for HS‐Het, 6thmonth for HS‐WT, 7thmonth for NS‐Het, 11thmonth for NS‐WT and 8thmonth for LS‐HET (132±3, 128±2, 125±3, 127±3 and 127±1 respectively, p<0.01 vs. baseline) but not for LS‐WT. Similar results were obtained for DBP (p<0.05), suggesting a volume mediated effect. The LS diet prevented the increase in BP only in WT mice.The A/C (μg/mg) was progressively increased in all groups, interestingly always preceding the BP change. Namely, A/C reached significance on the 3th,5th, 6th, 7th, 7th, 11thmonth for HS‐Het, HS‐WT, NS‐Het, NS‐WT, LS‐Het and LS‐WT (44±3,44±5, 35±2, 35±1, 38±3 and 40±2 respectively, p<0.05vs. baseline).PA and PRA were appropriately activated by dietary salt restriction and suppressed by aging.With the exception of LS‐WT (renal resistive index 0.69±0.01)., all groups developed renal resistanceConclusionsOur novel study showed that long‐term exposure to HS induced a progressive increase in BP in the WT, which was preceded by kidney damage. Interestingly in the LSD1‐Het, similar changes are initiated at an earlier age, suggesting that LSD1 is a critical component of mechanisms involved in CVR health.Importantly, the observed changes in BP and AC seem to be prevented by long‐term reductions in sodium intake in the WT. However, a stricter control of sodium intake was only able to delay and blunt the development of target‐organ damage and the hypertension in the LSD1‐Het model.Our study, performed in a clinically relevant animal model, suggest that LSD1 deficiency is a risk factor for cardiovascular and renal health, particularly during long‐term sodium loading, but also during moderately and severely restricted sodium diets.Support or Funding InformationFAPESP, CAPES and Amercian Heart AssociationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Multiple Poloxamers Improve Membrane Repair Capacity in a Model of Duchenne Muscular Dystrophy
Authors: Rose Aubrey , Kwiatkowski Thomas , McElhanon Kevin , Paleo Brian , Capati Ana , Beck Eric X , Weisleder Noah 
Published: June 2021

Muscular dystrophies, such as Duchenne Muscular Dystrophy (DMD), are characterized by severe muscle degeneration and weakness. A major contributor to this pathology is sarcolemmal membrane fragility, which leads to increased damage to muscle fibers. A potential therapeutic approach is to improve membrane repair, allowing cells to more effectively resist damage that otherwise leads to necrotic cell death. Previous literature demonstrates that use of Poloxamer 188 (P188) can increase membrane repair capacity due to its affinity for damaged cell membranes. P188 is part of a family of poloxamers, all of which consist of a hydrophobic region of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene. These chains vary in length between different poloxamers. While P188 has been extensively researched in terms of membrane repair, other poloxamers in the same family have not been tested in this capacity. Based on the similarities between these polymers, we hypothesized that other poloxamers in the P188 family will reseal membrane wounds as effectively as P188. To investigate this hypothesis, we first used a rotation damage assay, in which Human Embryonic Kidney (HEK293) cells were exposed to various poloxamers and injured through impact with small glass beads (106 m). After injury, the lactate dehydrogenase (LDH) level in the cell supernatant was measured and compared to no damage and no poloxamer controls. A laser injury assay was subsequently used to investigate the effects of poloxamers on both HEK293 cells and murine muscle fibers. For these experiments, cells were injured with a multiphoton laser in the presence of a lipophilic dye (FM4‐64), which fluoresces when it comes in contact with the lipids of the cell membrane. Change in fluorescence is measured over time to quantify changes in membrane repair capacity. Muscle fibers for the laser injury assay were taken from mdx mice, a mouse model of DMD. Results indicate that multiple poloxamers improve membrane repair capacity similarly to P188. Our results also suggest that certain poloxamers have this effect in a cell‐type specific manner. This investigation improves our understanding of the effect of poloxamer size and composition on membrane repair. Our results support these polymers as promising therapeutics for DMD and other diseases where necrotic cell death contributes to disease progression.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Imoxin, a PKR inhibitor, ameliorates ER stress induced by palmitate or tunicamycin in C2C12 myotubes
Authors: Eo Hyeyoon , Valentine Rudy J 
Published: June 2021

Prevalence of obesity has increased worldwide for decades and has becomes a major public health issue. Obesity is a key inducer of endoplasmic reticulum stress (ER stress), insulin resistance and sarcopenia. ER stress cause accumulation of unfolded or misfolded proteins leading to an unfolded protein response (UPR). Chronically prolonged ER stress consequently can interfere with insulin signaling and cell survival. The double‐stranded RNA (dsRNA)‐activated protein kinase R (PKR) plays a significant role in mediating inflammation, insulin sensitivity and glucose homeostasis. However, pathological roles of PKR in ER stress in muscle cells under obese condition is not fully understood. The current study aimed to investigate the effect of imoxin, a PKR inhibitor, on ER stress induced by palmitate or tunicamycin in C2C12 myotubes. The cells were treated with imoxin at 5 uM with or without bovine serum albumin (BSA)‐conjugated palmitate at 0.5mM or 500 ng/ml tunicamycin for 24 hr. Levels of ER stress signaling proteins including CHOP and BiP were measured by Western blotting. Palmitate significantly augmented the protein levels of both CHOP (288 ± 56%) and BiP (224 ± 17%) compared with BSA control. However, imoxin treatment attenuated palmitate‐induced ER stress signaling (140 ± 30% for CHOP and 89 ± 4% for BiP compared with control, respectively). Similarly, tunicamycin treated cells showed higher protein levels of CHOP (1132 ± 96%) and BiP (794 ± 34%) than control. Imoxin treatment prevented tunicamycin‐induced ER stress signaling (67 ± 40% for CHOP and 245 ± 27% for BiP compared with control, respectively). Thus, these results suggest that palmitate and tunicamycin induce ER stress through PKR in muscle cells.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Roles of Zip8 and Zip14 Transporters in Myogenesis
Authors: Gordon Shellaina Joy Victoria , Vest Katherine E , Padilla‐Benavides Teresita 
Published: June 2021

Transition metals like manganese (Mn) are necessary catalytic and structural cofactors in enzymes and as second messengers in cell signaling. Studies on the molecular mechanisms by which Mn contributes to development are focused on its role as co‐factor of the mitochondrial enzyme superoxide dismutase 2 (SOD2). However, Mn has been proposed to participate in protein glycosylation during bone and neural development. Our laboratory is investigating the biological relevance of Mn in the differentiation of skeletal muscle cells. During myogenesis, total mitochondrial content increases and cells increase expression of SOD2, which protects against oxidative stress. Our lab has shown that the gene and protein levels of ZIP8 and ZIP14, two membrane Zn/Mn transporters, increase during differentiation of the C2C12 immortalized mouse myoblasts. Preliminary data shows a significant increase in the cellular Mn quota during the differentiation of primary myoblasts derived from mouse satellite cells, which are the stem cell pool that sustains and regenerates myofibers in adult skeletal muscle. We hypothesized that ZIP8 and ZIP14 might be associated with the Mn influx during myogenesis. To determine the role of ZIP8, ZIP14, and Mn during myogenesis we used shRNA to delete Zip8 and Zip14 transporters in primary myoblasts derived from primary myoblasts. Partial deletion of these transporters resulted in changes in cellular Mn levels. Zip8 knockdown myoblasts are unable to differentiate compared to control and Zip14 knockdown myoblasts, as shown by the expression of muscle‐specific differentiation markers and alterations on the morphology of differentiating cells. Sod2 activity is reduced also in Zip8 knockdown myoblasts. This work will contribute considerably to the very limited literature related to Mn biology in myogenesis and would provide a foundation for future efforts to understand the contribution of Mn in other differentiation and disease models.Support or Funding InformationThis project was funded by the Faculty Diversity Scholars Award from the University of Massachusetts Medical School Awarded to TP‐B. S. Gordon is supported by the NIH Grant R25 HL092610‐11This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Comparison of Ischemia‐Reperfusion Injuries Induced by Tourniquet and Femoral Artery Ligation in Mouse Hindlimb
Authors: Qian Junliang , Tu Huiyin , Zhang Dongze , Wadman Michael C. , Li Yu‐Long 
Published: June 2021

The tourniquet and artery ligation are used widely to stop extremity hemorrhage or create a bloodless operating field. However, both of them also induce ischemia‐reperfusion (IR) injuries. To further evaluate the application of the tourniquet and artery ligation, we compared tourniquet and femoral artery ligation‐induced IR injuries in mouse hindlimb.C57/BL6 mice were anesthetized and 3 hours of unilateral hindlimb ischemia was induced by placing an orthodontic rubber band (ORB) at the hip joint or undergoing a surgery procedure of femoral artery ligation, then the ORB tourniquet or artery ligation was released for 24 hours of reperfusion. Immunohistochemistry data demonstrated that tourniquet‐induced IR caused severe skeletal muscle damage, compared to femoral artery ligation‐induced IR. Triphenyl Tetrazolium Chloride Assay further confirmed that the infarct size in the gastrocnemius muscle was higher in tourniquet‐induced IR mice than that in femoral artery ligation‐induced IR. Sciatic nerve‐stimulated gastrocnemius muscle contraction was weak in tourniquet‐induced IR mice (0 g), compared to femoral artery ligation‐induced IR (46.42±3.74 g). Tourniquet‐induced IR also resulted in more serious damage of lymphatic vessels in mouse hindlimb, compared to femoral artery ligation‐induced IR.Our present study indicate that tourniquet‐induced IR causes more severe skeletal muscle injuries than that induced by femoral artery ligation‐related IR.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.