bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimechanistic combination enhances selenium’s antiproliferative effect in prostate cancer cells (826.2)
Authors: Li Xiuqi , Manwaring Eliza , Hopkins Tyler , Worden Joseph , Schille Colton , Eggett Dennis , Lawson John , Christensen Merrill 
Published: June 2021

The anti‐cancer activity of selenium (Se) has been demonstrated by multiple in vitro and in vivo studies. However, none have sought to combine different forms of Se, with their varied mechanisms, to enhance Se’s chemopreventive efficacy. In this study, we hypothesized that systematically blending multiple forms of Se will produce a pleiotropic, multimechanistic combination that optimizes the in vitro growth inhibition of PC‐3 cells. In order to accomplish this, we first determined the IC50s of methylseleninic acid (MSA), sodium selenite, and Se nanoparticles (nano Se) via Alamar Blue proliferation assay. They were 5.0 μM, 14.0 μM, and 14.6 μM, respectively. We then utilized mixture designs and response surface methodology to direct our combination experiments: 10 combinations of MSA, sodium selenite, and nano Se were selected, each equaling 10 μM Se total. Experimental data of these 10 combinations were used to construct a polynomial model. This mathematical model predicted the optimum combination of the these Se compounds in inhibiting PC‐3 cell growth to be 4.1 μM of MSA, 5.1 μM of sodium selenite, and 0.8 μM of nano Se. These data provide proof of principle that combinations of different Se compounds exhibit greater chemopreventive efficacy than individual Se agents.Grant Funding Source: Supported by NIH CA122235 to MJC and BYU Cancer Research Center Fellowship to XL.
Influence of folate on lipid accumulation in human primary subcutaneous adipocytes (827.8)
Authors: Hausman Dorothy , Alvis Courtney , Bailey Lynn , Park Hea Jin 
Published: June 2021

Epidemiological studies report inverse associations between serum folate concentrations and body mass index, however the potential influence of changes in folate status on adipose cell development and metabolism has only been examined in animal models or a murine cell line. The objective of this study was to determine the influence of alterations in folate availability on differentiation of human primary preadipocytes. Human primary preadipocytes, derived from subcutaneous adipose tissue of normal weight female donors (ZenBio Inc), were exposed to 0.06, 6 or 60 uM folic acid (FA; Sigma), 5‐methyltetrahydrofolate (MTHF; Merck) or tetrahydrofolate (THF; Merck) during the differentiation period. The impact of treatment on lipid accumulation was determined using AdipoRedTM Adipogenesis assay reagent (Lonza). Results indicate that FA, MTHF and THF decreased lipid accumulation in mature adipocytes, after adjusting for cell number. Interestingly, MTHF and THF, reduced forms of folate, exhibited a greater inhibitory effect on lipid accumulation. These results indicate that biologically active reduced forms of folate may have a greater effect on adipocyte differentiation in human adipocytes. This study also supports preliminary findings in murine cell lines demonstrating an effect of changes in folate availability on adipose cell development.Grant Funding Source: Funded in part by HATCH #GEO00707. MTHF and THF were a kind gift from Merck & Cie, Switzerland.
Cinnamon polyphenols increase oxygen‐glucose deprivation of decreased PGE2 production by upregulation of SIRT1 and alleviation of the anti‐inflammatory effects (830.11)
Authors: Qin Bolin , Anderson Richard 
Published: June 2021

Prostaglandin E2 (PGE2) is an important mediator of many biological functions, including vasodilation, both anti‐ and proinflammatory actions, and modulation of sleep/wake cycles. It is well known that cinnamon polyphenols have anti‐oxidant properties and that oxidative stress damages endothelial cells. We investigated the mechanisms underlying protective effects of an aqueous extract of cinnamon, high in polyphenols, in 3 hr oxygen‐glucose deprivation (OGD) treated mouse brain microvascular endothelial (bEnd.3) cells. Immunoprecipitation/Western blotting and immunofluorescent analyses showed that OGD/reperfusion down regulated PGE2 secretion into the media and cellular PGE2 expression. Cinnamon polyphenols reversed these damages and also induced sirtuin (SIRT)1 expression. Further studies showed that the effects were reversed by a SIRT1 inhibitor IV. Cinnamon polyphenols also inhibited the expression of the anti‐apoptotic protein, Bcl‐xl, and induced the expression of the pro‐apoptotic protein, Bax, in OGD treated cells. The OGD‐induced inflammatory factors, TNF‐α and phospho‐Nf‐kB p65, were suppressed by cinnamon polyphenols. Taken together, these results suggest protective roles of cinnamon on PGE2 production and that cinnamon polyphenols may be neuroprotectants for ischemia‐related injury.Grant Funding Source: This work was supported in part by a USDA Cooperative Research and Development Agreement (CRADA No.5
The metabolic challenge induced by hypercaloric diet leads to increased activity of the HPA axis and cardiac autonomic dysfunction in rats with low glial angiotensinogen (831.3)
Authors: de Lima Daniel , Nascimento kenia , Shaltout Hossam , Coimbra Candido , Diz Debra 
Published: June 2021

We assessed the effect of metabolic challenge induced by hypercaloric diet on neuroendocrine parameters, renin‐angiotensin system components and heart rate variability (HRV) in transgenic rats with low glia‐derived angiotensinogen [TGR(ASrAogen)]. ASrAogen rats were fed with chow diet (AO, n=12) or hypercaloric diet (AO‐HD, n=14) from 4 to 13 wks of age. Sprague Dawley rats served as controls (SD, n=15; SD‐HD, n=13). AO‐HD displayed two fold increases in circulating angiotensin II and ACTH compared to AO (p<0.05). Both AO groups had higher levels of circulating corticosterone (200%, p<0.05). In addition, AO‐HD animals exhibit elevated resting mean arterial pressure (AO‐HD, 93 + 2 mmHg; AO, 74 + 3 mmHg; p<0.05), associated with impaired baroreflex sensitivity (42%, p<0.05). Furthermore, AO‐HD had lower vagal (Seq up, 48%; HF alpha, 41%; p<0.05) and sympathetic (Seq Down, 35%; LF alpha, 55%; p<0.05) indices for control of HR. To summarize, ASrAogen rats under metabolic challenge exhibit elevated arterial pressure and cardiac autonomic imbalance, accompanied by increased circulating angiotensin II and increased activity of the HPA axis. We concluded that the glial renin‐angiotensin system is important for regulation of neuroendocrine and cardiac function in response to metabolic challenge induced by hypercaloric diet. Support: CNPq; NIH HL51952Grant Funding Source: CNPq; NIH HL51952
The role of adiponectin in high‐fat mediated cardioprotective programs (837.5)
Authors: Wani Mashhood , Haar Lauren , Amratia Avni , Gonzalez Christopher , Jones W.K. 
Published: June 2021

The heart protects itself from injury through protective intrinsic mechanisms. Understanding the mechanisms that elicit this cardioprotective effect is vital to the prevention of myocardial infarction. It has been established in the Jones Lab that an acute high fat diet elicits a cardioprotective effect in a murine model. The adipose‐derived circulating adipokine adiponectin may play a crucial role in the activation of cardioprotective gene programs in this high fat model as it has been previously shown to be cardioprotective. This study will address the hypothesis that high fat diet mediates cardioprotection through circulating adiponectin acting through receptors in the heart that activate autophagic and anti‐apoptotic programs necessary for preconditioning.To address this hypothesis, an in vitro model was established by simulating I/R in HL‐1 cells, and a surgical model that utilizes 30 minute occlusion of the LAD to create infarct. Beclin‐1 (a marker of autophagy) expression was assessed in mice after a 24hr high fat diet through western blot analysis.From these results, we are able to establish that an acute high fat diet elicits a cardioprotective effect in a murine model. Furthermore, the cardioprotective effect of the high fat diet is lost in adiponectin knockout mice, meaning that adiponectin is a key player in high fat mediated cardioprotection. The upregulation of Beclin‐1 after a high fat diet suggests that adiponectin and the high fat diet is priming the cells for an autophagic state. Beclin‐1 is a downstream target of NF‐κB, a key player in cardioprotective mechanism, and this suggests that adiponectin is interacting with NF‐κB and eliciting a cardioprotective effect.Grant Funding Source: Provost Pilot Grant‐University of Cincinnati(COM)
The role of dopaminergic signaling in Daphnia magna swimming (839.5)
Authors: Barrozo Enrico , Fowler David , Ingebretson Justin , Beckman Matthew 
Published: June 2021

Daphnia are freshwater crustaceans that have been used for decades in ecotoxicology research. In order to determine the role of dopamine in Daphnia movement we have carried out a screen of 10 dopamine receptor drugs; three drugs affected movement. To screen for drug effect on behavior in Daphnia we have developed a two‐dimensional video imaging system to measure the movement of Daphnia magna swimming in shallow circular‐well plates. At one, two, and six hours of treatment with 10µM drug, the D1‐like receptor agonist (1R,3S)‐1‐(Aminomethyl)‐3‐phenyl‐3,4‐dihydro‐1H‐isochromene‐5,6‐diol (A68930), the D2‐like agonist (5'a)‐2‐Bromo‐12'‐hydroxy‐2'‐(1‐methyl舃ethyl)‐5'‐(2‐methylpropyl)ergotaman‐3',6',18‐trione mesylate (bromocriptine), and the D4‐like receptor antagonist 3‐(4‐[4‐Chlorophenyl]piperazin‐1‐yl舃)‐methyl‐1H‐pyrrolo[2,3‐b]pyridine trihydrochloride (L‐745, 870) all decreased movement with different time‐courses of inhibition. For two of the drugs which exhibited significant effects on daphnid behavior at one hour of treatment, A68930 and bromocriptine, the IC50 values were determined to be in the low micromolar range. Preliminary results from experiments with the dopamine neurotoxin 1‐Methyl‐4‐phenylpyridinium iodide (MPP+) are consistent with a previous study showing 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) treatment decreased Daphnia swimming behavior. Last, we have performed genome mining studies which have identified a suite of dopaminergic genes in the Daphnia magna genome. Taken together, the data provide evidence that specific dopamine signaling pathways are involved in Daphnia swimming behavior. We propose that Daphnia is a useful model to use in studies of dopaminergic signaling in healthy and neurotoxin‐induced disease states.Grant Funding Source: Supported by The Augsburg URGO, McNair, and NorthStar STEM Programs and the College Dean's Office
GI‐safe NSAIDs and the suppression of colon cancer (840.5)
Authors: Lichtenberger Lenard , Waters David , Phan Tri , Dial Elizabeth 
Published: June 2021

The consumption of NSAIDs is linked with a reduction in cancer incidence, metastasis, and mortality. Our lab has developed a family of phosphatidylcholine (PC)‐associated NSAIDs which have reduced GI toxicity both in animals and humans, while possessing full COX‐inhibitory activity. This study was designed to test whether PC‐NSAIDs may also possess significant chemopreventive action. Methods: 1) MC‐26 colon cancer cells were incubated for 24 hours with (0.1‐2mM) of: Aspirin‐PC, or Ibuprofen‐PC; and 2) Sprague‐Dawley rats were inoculated with the carcinogen, azoxymethane (AOM), followed by daily oral NSAID dosing (20 mg NSAID/kg) and after 4 weeks the animals were evaluated for GI toxicity and colonic aberrant crypt formation (ACF). Results: Each of the PC‐NSAIDs showed direct inhibitory effects on growth of MC‐26 cells at 0.5‐1 mM. In vivo, both Aspirin‐PC and Ibuprofen‐PC significantly reduced colonic ACF in rats pre‐treated with AOM without evidence of GI toxicity. Conclusion: Both Aspirin‐PC and Ibuprofen‐PC demonstrated a direct inhibitory effect on the growth of colon cancer cells in vitro and in carcinogen/AOM‐treated rats, significantly reduced the development of colonic ACF, which is a precursor of colonic dysplasia and cancer, suggesting the potential utility of PC‐NSAIDs in patients at risk for colon cancer/recurrence. Supported by R03 CA 171613 and R41 CA171408.Grant Funding Source: NIH R03CA171613; R41 CA171408
Glucocorticoid signaling mediates stress‐induced impairment of neurovascular coupling (841.4)
Authors: Longden Thomas , Dabertrand Fabrice , Hammack Sayamwong , Nelson Mark 
Published: June 2021

Stress influences the progression and severity of many diseases. Here we examined the effects of stress on neurovascular coupling (NVC), which matches cerebral blood flow increases to local neuronal activity. NVC was studied in brain slices from the amygdala, where dilation of parenchymal arterioles (PAs) was measured in response to neuronal stimulation.We administered a 7‐day stress paradigm to male Sprague‐Dawley rats, resulting in anxiety‐like behavior and attenuated weight gain. After stress, PA vasodilation evoked by neuronal stimulation was reduced by 66%. This reduction was similar to that previously reported for the effect of blocking inward rectifier K+ (Kir) channels during NVC1. Indeed, blocking Kir channels with barium inhibited NVC in control but not stressed slices. We thus hypothesized that the impairment of NVC by stress reflects a loss of PA Kir channels. Consistent with this, we found that Kir channel current density in smooth muscle cells from PAs was reduced by 90%. Moreover, elevation of external K+ from 3 to 8 mM, which normally causes profound dilation of PAs through Kir activation, was almost without effect on arterioles from stressed rats. In vivo delivery of corticosterone (without stressors) or the glucocorticoid receptor blocker RU486 (prior to stressors) mimicked or prevented NVC impairment by stress, respectively.We conclude that stress causes a glucocorticoid‐mediated decrease in functional Kir channels in PA myocytes in the amygdala. This renders arterioles less responsive to K+ released from endfeet during NVC, thus impairing vasorelaxation. These studies may pave the way for the development of novel treatment options for brain disorders with a stress component.1. Filosa et al. (2006) Nat Neurosci 9(11): 1397‐1403Grant Funding Source: Supported by National Institutes of Health and the American Heart Association.
Does cigarette smoke exposure contributes to the progression of ovarian cancer? (844.7)
Authors: Sumanasekera Wasana , Conzelman Robert , Beckmann Taralein , Nguyen Lena , Petty Kayla , Kakar Sham 
Published: June 2021

Rationale and Objective: Investigating risk factors for ovarian cancer is at extreme importance due to the asymptomatic nature of this disease during early stages. Although a correlation between history of cigarette smoking in women and risk of ovarian cancer occurrence has been reported, there is no primary literature linking cigarette smoke (CS) as a causative factor in ovarian cancer development. Here we conducted an in‐vitro approach to detect effects of CS exposure on ovarian cancer progress. We hypothesized that cigarette smoke exposure cause promotion of ovarian cancer via attenuating apoptosis and increasing proliferation of cancer cells. Methods: A2780 ovarian cancer cells were used as the experimental model. Cigarette smoke extract (CSE) was created using a modification of a published method. Following serum starvation, A2780 cells were treated with either control (serum free media) or different concentrations of CSE for 24 hours. To detect effects of CSE on ovarian cancer cell apoptosis, apostain and tryphan blue exclusion assays were performed. To detect CSE effects on cell proliferation, BrdU cell proliferation assay was conducted. Results: 24 hour Exposure of CSE caused increase in cancer cell proliferation, and decrease in cancer cell apoptosis. Conclusions: CS promotes ovarian cancer progression via accelerating cancer cell proliferation and attenuating apoptotic cell death.Grant Funding Source: Sullivan University Faculty Development Grant
Cholesterol accumulation in skeletal muscle: a potential novel targetable pathway in insulin resistance (854.11)
Authors: Llanos Paola , Contreras‐Ferrat Ariel , Osorio César , Espinosa Alejandra , Hidalgo Jorge , Hidalgo Cecilia , Jaimovich Enrique 
Published: June 2021

Cholesterol is enriched in the skeletal muscle transverse tubule system, where translocation of GLUT4 glucose transporters takes place in response to insulin. We tested whether feeding mice a high fat diet (HFD), besides producing insulin resistance, increased TT cholesterol content and modified insulin‐induced glucose uptake. Male C57BL/6J mice were fed a normal or a HFD (60% fat) for 8 weeks. HFD‐fed mice displayed higher body weight and insulin resistance. Insulin‐stimulated glucose uptake in fibers from HFD‐fed mice was lower than in controls whereas cholesterol levels in triads from HFD‐fed mice were 30% higher. Pre‐incubation with Methyl‐β‐cyclodextrin (MβCD) reduced Akt phosphorylation and increased both basal and insulin‐induced glucose uptake in muscle fibers from controls or HFD‐fed mice. MβCD treatment restored normal glycemia and insulin sensitivity in HFD mice. Indinavir, a GLUT4 antagonist, inhibited the effects of MβCD. MβCD increased membrane GLUT4 content and elicited intracellular calcium signals inhibited by Dantrolene. Dantrolene also reduced MβCD‐mediated glucose uptake. These results provide a rationale for the clinical evaluation of cyclodextrins, as an approach to the treatment of insulin resistance and the control of diabetes.Grant Funding Source: ACT 1111, Fondecyt 3110105, 11130267, 11090301
Quantum dots reveal endothelial NOX2 induces VCAM expression in LPS‐challenged inflamed whole lung (855.2)
Authors: Orndorff Rebecca , Hong Nan Kang , Yu Kevin , Zern Blaine , Feinstein Sheldon , Fisher Aron , Muzykantov Vladimir , Chatterjee Shampa 
Published: June 2021

Quantum Dot (QD) technology coupled with fluorescence imaging is a powerful tool to detect cellular proteins in vivo. Here we employ QDs as an imaging tool to detect vascular cell adhesion molecule‐1 (VCAM) expression in a model of lung inflammation. A key event in inflammation is the expression of VCAM. VCAM induction is reportedly responsible for the accumulation of neutrophils in lungs and for subsequent production of reactive oxygen species (ROS). NADPH oxidase 2 (NOX2), expressed by both endothelial cells and neutrophils, is a major contributor to ROS production post inflammation in the lungs. To date, the cellular sources of NOX2 (neutrophils or endothelium) that regulate VCAM expression in inflamed lungs is unknown. Using QD probes specific for VCAM, we found increased VCAM expression post LPS‐challenge in vitro, which was abrogated by the NOX2 inhibitor, apocynin. Ex vivo and in vivo lungs exhibited an 8‐10 fold higher incidence of VCAM expression in LPS‐challenged lungs over NOX2 null lungs. We next employed an endothelial specific NOX2 expressing transgenic mouse in a NOX2 null background (endoNOX2Tg) to reveal that endothelial NOX2 induces VCAM expression at levels that are intermediate between those expressed in wild‐type (WT) and NOX2 null mice. This result indicates that endothelial NOX2 is sufficient to induce VCAM expression due to an inflammatory stimulus.Grant Funding Source: Supported by T32‐HL07748.
Discordant neurohumoral responsiveness to orthostatic stress in amenorrheic physically active premenopausal women (858.4)
Authors: O'Donnell Emma , Goodman Jack , Mak Susanna , Floras John , Morris Beverley , Harvey Paula 
Published: June 2021

In light of the known modulatory effects of estrogen on neurohumoral control of blood pressure (BP), we tested the hypothesis that muscle sympathetic nerve activity (MSNA) and serum renin angiotensin aldosterone system (RAAS) levels would differ between estrogen deficient physically active women with functional hypothalamic amenorrhea (ExFHA) and eumenorrheic estrogen replete women. MSNA, serum RAAS components (renin, angiotensin II and aldosterone), and brachial artery BP (mmHg) were recorded at baseline and during graded lower body negative pressure (LBNP; ‐10, ‐20, and ‐40mmHg) in 17 recreationally active eumenorrheic women (ExOv; 24±1 years; body mass index 20.9±0.5kg/m2; mean±SEM) and 12 ExFHA women (25±1 years; 20.7±0.7 kg/m2). At baseline, heart rate (HR; b/min) and systolic BP (SBP) were lower (p<0.05) in ExFHA (47±2 and 94±2, respectively) compared with ExOv (56±2 and 105±2) women. Baseline MSNA, RAAS components, and mean arterial BP (MAP) were similar (p>0.05) between the groups. In response to graded LBNP, HR was increased (p<0.05) and SBP decreased (p<0.05) in both groups, but responses were lower (p<0.05) in ExFHA women. MSNA (bursts/100 heart beats) increased in both groups, but responses were greater (p<0.05) in ExFHA than ExOv women at ‐20 and ‐40 mmHg (37±4 vs. 22±4; 45±4 vs. 33±4, respectively). LBNP elicited increases (p<0.05) in all RAAS components in ExOv, but not ExFHA, women (p>0.05). In conclusion, these findings suggest that in hypoestrogenic ExFHA women, sympathetic nerve activity, but not the RAAS, defends arterial BP during orthostatic stress.Grant Funding Source: Supported by a Cardiovascular Independent Research Award (NRA 3840028) awarded from Pfizer
Specific inhibition of AT1‐AAs by direct binding improves maternal and fetal outcome in response to placental ischemia during pregnancy: emphasizing the importance of novel drug development in the treatment of preeclampsia (860.15)
Authors: Moseley Janae , Castillo Javier , Amaral Lorena , Cornelius Denise , LaMarca Babbette 
Published: June 2021

Preeclampsia, (PE) hypertension with proteinuria during pregnancy, is associated with antibodies that activate the angiotensin II receptor (AT1‐AA). Infusion of AT1‐AA increases blood pressure (MAP) and causes many characteristics of PE in pregnant rodents. The objective of the study was to determine if specific inhibition of AT1‐AA improves pregnancy outcomes in RUPP pregnant rat model of PE.Specifically AT1‐AA inhibitory peptide (2ug/ml saline) was infused via miniosmotic pumps into RUPP rats beginning day 14 of gestation, immediately following the RUPP procedure. On day 19 blood pressure, MAP, blood and tissue were collected.MAP was 99+/‐2 in NP(n=18), 121+/‐2 in control RUPP rats (n=19;P<0.001) and was 109 +/‐6 mmHg (n=9 P<0.02) in RUPPs + AT1‐AA inhibitory peptide. Pup weight in NP was 2.4 +/‐ 0.04 in NP; 1.9 +/‐ 0.06 in RUPP, improved significantly to 2.2 +/‐ 0.14 g (P<0.05) in RUPPs + AT1‐AA inhibitory peptide.These studies indicate that specific AT1‐AA inhibition improves maternal blood pressure and fetal outcome in response to placental ischemia, thereby emphasizing the importance of drug discovery for AT1‐AA inhibition to improve pregnancy outcomes in preeclamptic patients.Grant Funding Source: Ferring Pharmaceuticals, NIH NICHD