bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic effect of CLA isomers on bone mineral density, fat and lean mass in C57BL/6 female mice
Authors: Halade Ganesh Vasantrao , Rahman Md Mizanur , Banu Jameela , Fernandes Gabriel 
Published: June 2021

Conjugated linoleic acids (CLA) are a class of positional, geometric, conjugated dienoic isomers of linoleic acid (LA). Dietary CLA supplementation results in a dramatic decrease in body fat mass and increase in lean mass as well as protects against bone loss both in mice and humans. However, little information is known of the long term effect of CLA isomers in animals as well as in humans. In order to investigate the isomer specific effects of CLA on fat and lean mass, the purified c9,t11‐CLA, (0.5%), t10,c12‐CLA (0.5%) and CLA‐mix (0.25%, c9,t11‐CLA + 0.25% t10,c12‐CLA) were fed along with 10% corn oil (CO) to 6 months old C57BL/6 female mice (n=8–10) for 6 months. All of the dietary interventions of CLA groups were compared with CO fed mice as a control group. After 6 months, mice were scanned using DEXA to measure the bone mineral density (BMD), lean and fat mass. The results revealed that, the body weights were significantly decreased in both t10,c12‐CLA, CLA‐mix groups compared to c9,t11‐CLA and 10% corn oil. Further, t10,c12‐CLA and CLA‐mix groups significantly decreased the total and abdominal fat mass compared to c9,t12‐CLA and CO group. In addition, both CLA‐mix and t10,c12‐CLA significantly increased the lean mass and also BMD in lumbar spine and distal femoral metaphysis compared to corn oil. The overall % fat of the body were decreased significantly in t10,c12‐CLA and CLA‐mix compared to c9,t11‐CLA and CO group. In conclusion, the specific effect of t10,c12‐CLA induces both significant fat mass reduction, maintains higher lean and bone mass compared to c9,t12‐CLA and CO.Research support: NIH R21 AG027562
Probucol impairs cardiac function in apo E‐KO mice
Authors: Moghadasian Mohammed H , Othman Rgia , Jassal Davinder , Fang Tielan , Zhao Zhaohui , Kroeker Amy , Riediger Natalie , Xu Zuyuan , Walker Kristy , Le Khoung , Azordegan Nazila 
Published: June 2021

Background: Despite beneficial cholesterol‐lowering and antioxidant properties of probucol, it paradoxically increases coronary atherogenesis in apo E‐KO mice. The aim of this study was to investigate the effects of probucol on cardiac function in apo E‐KO mice.Materials and Methods: Male apo E‐KO and C57BL/6 mice were fed an atherogenic diet with (treated, n=8) or without (control, n=8) 1% probucol for 16 weeks. Plasma cholesterol levels were measured. Murine echocardiography was performed serially at 6 week intervals.Results: Probucol treatment resulted in significant reductions in plasma cholesterol levels in both apo E‐KO (−30%, p<0.05) and C57BL/6 mice (−90%, p<0.01). Apo E‐KO mice treated with probucol showed early regional LV systolic dysfunction as early as 6 weeks with further decrease over time [endocardial velocity −40%; strain −40%, ejection fraction −10% (p<0.01)], with no impact on mortality. Such effects of probucol were not observed in C57BL/6 mice.Conclusions: Probucol impairs cardiac function in apo E‐KO mice. This may be related to previously observed coronary atherogenesis due to probucol in this animal model.Supported in part by URGP, HSF and NSERC.
Effect of nicotinic acid on plasma lipid and hepatic gene expression in obese insulin resistant dogs.
Authors: Le Bloc'h Jérôme , Leray Véronique , Zaman Muhamad‐Quaid , Serisier Samuel , Ouguerram Khadija , Nguyen Patrick 
Published: June 2021

Nicotinic acid (NA) is well known for improving plasma lipids in man (decrease in triglycerides (TG), total (TC) and LDL‐cholesterol (LDL‐C) and increase in HDL‐cholesterol (HDL‐C) levels). The aim of this study was to assess the effects of NA in obese insulin resistant dogs.Eight beagle dogs were alloted to 2 groups : treated (n=5) and control (n=3). Treated dogs were given 375mg/d of NA for one week and then 500mg/d for 3 weeks. Insulin sensitivity, plasma TG, TC, free fatty acids and insulinemia were assessed at the end of the experimental period. Plasma lipoproteins were separated, and LDL‐C or HDL‐C were measured. Hepatic expression of ABCA1 and SR‐BI was quantified using real‐time RT‐PCR.NA treatment did not induce any change in either insulin sensitivity or glycemia, insulinemia and free fatty acid concentrations. In the treated group, TG were reduced by 30% (p < 0.05), and TC by 25% (p < 0.001). Analysis of lipoprotein cholesterol showed a reduction in LDL‐C (p < 0.05) whereas HDL‐C was unchanged. All these parameters were unchanged in the control group. No change in the ABCA1 and SR‐BI expression was observed in liver.Our results confirm the effects of NA that have been described in humans, except that concerning the increase in HDL‐C. According to observations recently done in mice, as dogs are devoid of CETP activity, we can hypothesize that CETP might be the link between plasma TG decrease and change in HDL‐C.
Effects of endurance exercise training on endothelial function and atherosclerosis in the hereditary hypercholesterolemic swine model
Authors: Newcomer Sean , Roseguini Bruno , Esquivel Arturo Arce , Bender Shawn , Turk James , Laughlin Harold 
Published: June 2021

Hereditary hypercholesterolemic (HH) swine develop advanced atherosclerotic lesions throughout the coronary and peripheral vasculatures. The purpose of this study was to test the hypothesis that endurance exercise training would increase endothelial function and decrease the prevalence of atherosclerosis in this swine model. Ten adult pigs were randomly assigned into either exercise trained (EX) or sedentary groups (SED). Exercise training consisted of 16 weeks of treadmill running. Upon sacrifice the following arteries were harvested: thoracic aorta (TA), carotid (CA), brachial (BR), femoral (FEM) and coronary arteries (LAD, RCA, CFX). In vitro assessment of endothelium‐dependent dilation (EDD) was determined by administering increasing doses of acetylcholine to BR and FEM rings and bradykinin to CFX rings. Atherosclerotic lesion formation was quantified through Sudan IV staining in the TA, CA, BR, FEM, LAD and RCA. Endurance exercise training increased EDD in the BR and FEM but not in the CFX. The percentage of Sudan IV staining was not significantly different between EX and SED swine in the TA, CA, BR, FEM, RCA and LAD arteries. These findings demonstrate that endurance exercise training increases EDD in the BR and FEM arteries, but does not alter the development of atherosclerosis in HH swine.Supported by NIH HL083597, HL36088 and HL52490
Effects of acute exercise on endothelial nitric oxide synthase (eNOS) in rat vasculature
Authors: McAllister Richard Murray , Weimer Cory Matthew 
Published: June 2021

eNOS is phosphorylated by shear stress in cultured endothelial cells; whether eNOS phosphorylation occurs in vivo is unknown. We hypothesized that acute exercise induces phosphorylation of eNOS via the protein kinase Akt. Rats were either cage‐confined (Sed, n=4) or run on a treadmill for 30 min (Ex, n=4). Endothelial proteins were extracted from each rat aorta in a buffer containing the phosphatase inhibitor calyculin (100 nM). NOS activity ([3H]‐L‐arginine assay) did not differ (P>0.10) between Sed and Ex (Sed, 1001±200 fmol/mg/h; Ex, 1269±150). Phosphorylated eNOS (Ser1177; Western blotting) also did not differ between groups (Sed, 1017±141 units; Ex, 879±216). Phosphorylated Akt (Ser473) was not detected in most vessels; phosphorylated protein kinase A (PKA; Thr198) was detected (Sed, 886±242 unts; Ex, 1496±210; 0.05<P<0.10). These data suggest that levels of shear stress at rest are sufficient to phosphorylate eNOS at Ser1177. Further, they may indicate that PKA rather than Akt is the mediator of eNOS phosphorylation in vivo.Supported by NIH RR1 8276 and a Faculty Research Award from the College of Veterinary Medicine, University of Missouri.
Events leading to intestinal barrier failure and systemic inflammation following hemorrhagic shock
Authors: Thuijls Geertje , Derikx Joep P , de Haan Jacco‐Juri , Hadfoune M’hamed , Heineman Erik , Buurman Wim A 
Published: June 2021

Hemorrhagic shock (HS) leads to systemic inflammatory response syndrome (SIRS), a potential deleterious complication. A current hypothesis states that gut barrier loss is crucial in the development of SIRS. We aimed at elucidating the sequence of events leading to gut barrier loss and SIRS following HS.Rats were subjected to HS and sacrificed at 15, 30, 60, 90 min after HS, and compared with sham controls. Intestinal neutrophil influx (NI), tight junction (TJ) integrity, enterocyte integrity, bacterial translocation (BT), and SIRS were assessed.HS leads to early NI from 15 min after HS, followed by a significant loss of TJ proteins Claudin‐3 and ZO‐1 from 30 and 60 min after HS, respectively (100% versus 71% and 100% versus 41%, respectively, P<0.05, students t‐test (stt)). Enterocyte integrity loss measured by plasma Ileal Lipid Binding Protein levels, is markedly increased from 60 min after HS (0.6 versus 11.8 ng/ml, P<0.0001, stt). Intestinal barrier function loss detectable from 60 min after HS is represented by BT (0.0 versus 47.9 CFU/g tissue, p<0.005, wilcoxon signed rank test (wsrt)). SIRS measured by plasma TNFα levels is significantly elevated from 60 min after HS (0.0 versus 26.1 pg/ml, p<0.05, wsrt).HS leads to NI and gut barrier integrity loss, followed by BT and SIRS within 90 min after shock. Ongoing studies are directed at unraveling the causal relation between succeeding events.
Imbalance angiogenesis regulators: A novel explanation for poor ulcer healing
Authors: Deng Xiaoming , Szabo Sandor , Khomenko Tetyana , Xiong Ximing , Sandor Zsuzsanna , Osapay Klara , Jadus Martin R. , Tostanova Ganna , Chen Longchuan 
Published: June 2021

We tested the hypothesis that an imbalance in angiogenic and anti‐angiogenic factors may play an important role in development and delayed healing of duodenal ulcers induced by duodenal ulcerogens cysteamine or propionitrile in rats. Scrapings of proximal duodenal mucosa were collected to study gene expression of collagen XVIII by microarray and Real‐time PCR, proteolytic activity of matrix metalloproteinases (MMP) by zymography and ELISA, and levels of angiostatin, endostatin and VEGF by Western blot and ELISA. Additional groups of rats were daily given endostatin for 3 and 7 days after cysteamine to test the effect of endostatin on ulcer healing. The results showed increased endostatin and angiostatin accompanied by elevated MMP2 activity in the early or late stages of ulceration, when VEGF levels were also markedly increased. Endostatin treatment significantly delayed duodenal ulcer healing. Conclusions: 1) Both anti‐angiogenic factors angiostatin/endostatin and angiogenic factor VEGF were upregulated in experimental duodenal ulceration. 2) Excess of anti‐angiogenic factors, e.g., endostatin and angiostatin may be one of important mechanisms in impaired ulcer healing. 3) Thus, an imbalance of angiogenesis regulators seems to be a new element in ulcer pathogenesis and healing.(The present study was supported by a Department of Veterans Affairs, Veterans Health Administration Merit Review grant and by contributions from CPRC, Inc.)
Proteomic profiles of liver microsomes from mice treated with the hepatotumorigenic conazole, triadimefon
Authors: Ortiz Pedro A. , Chen Pei‐Jen , Moore Tanya , Nesnow Stephen , Winnik Witold M. 
Published: June 2021

Triadimefon is a triazole‐based conazole fungicide used in agriculture. This conazole is hepatotoxic and hepatotumorigenic in mice. As part of a large study aimed at determining the mechanism(s) of action of tumorigenic conazoles we have performed a comparative proteome analysis of liver microsomes from mice exposed to triadimefon. Liver microsomes from male CD‐1 mice exposed to tumorigenic doses of triadimefon for 4 days by intraperitoneal injection were prepared. Protein level changes were examined by a 2D difference gel electrophoresis (DIGE) and were identified by nanospray‐liquid chromatography‐tandem mass spectrometry (LC‐MSMS). Seventy‐eight proteins that have shown changes in expression have been identified; the pathways affected by these proteins are the metabolism of xenobiotics by cytochrome P450, proteasome, and the metabolism of glutathione, nitrogen, and glutamate. In addition, we have developed a reverse‐phase protein method to improve mass spectral detection and identification of microsomal cytochrome P450s and UDP‐glucuronosyltransferases proteins, which is being used to monitor changes of hydrophobic proteins that are poorly represented in 2‐D gels. Correlation of the conazole effects on protein expression with toxicology and genomic data will contribute to the elucidation of its mode of action.This is abstract does not necessarily reflect EPA policy.
Freeze‐Frame Click‐Chemistry Synthesis on a Soluble Alpha‐7 Nicotinic Acetylcholine Receptor (nAChR) Ligand Binding Domain
Authors: Nemecz Akos , Talley Todd , Fotsing Joseph , Weide Timo , Grimster Neil , Ho Kwok‐Yiu , Fokin Valery V. , Sharpless K. Barry , Taylor Palmer 
Published: June 2021

The cys‐loop family of ligand‐gated ion channels plays an important role in the chemical‐to‐electrical transduction of neuronal signaling. The well‐studied α7‐nAChR may be linked to nicotine addiction, and shows possible genetic linkages to such diseases as Alzheimer's and schizophrenia. The discovery of a homologous soluble snail acetylcholine binding protein (AChBP) provided a structural surrogate of the extracellular ligand‐binding domain; however, the binding protein, despite the requisite ligand properties, shows only 30% residue identity with the nicotinic receptor family. Thus, creating a soluble human extracellular domain with the residues of various receptor subtypes would greatly aid in finding selective drug targets. Accordingly, we systematically mutated soluble Aplysia californica towards the α7‐nAChR, simultaneously analyzing binding affinities. Key expressing constructs were subsequently characterized using classical α7‐nAChR selective ligands such as α‐bungarotoxin, (+)‐epibatidine, and methyllycaconitine. After the characterization and determination of a soluble template freeze‐frame “click” chemistry was applied using weak binding chemical building blocks to create a selective moderate affinity ligand.Support: R37‐GM18360; U01‐NS043063
NO‐dependent Molecular Mechanism in Relaxing Effect of Cilnidipine (CIL) in Human Internal Mammary Arteries (IMA)
Authors: Fan Li , Xiao Xiao‐qiu , Grove Kevin , Huang Yu , Yang Qin , Furnary Anthony , He Guo‐Wei 
Published: June 2021

CIL, the novel long‐lasting L/N‐type dihydropyridine calcium channel blocker, induces both endothelium‐dependent and independent relaxation in human IMA. We investigated the underlying molecular mechanism on nitric oxide (NO)‐cyclic guanosine monophosphate (cGMP) pathway. The expression level of eNOS mRNA in IMA incubated with/without (n=5/6) 3 μ CIL for 30 min followed by 10 μM norepinephrine (NE) stimulation for 4 hrs was assayed by Real‐Time quantitative PCR. The phosphorylation of eNOS at Ser1177 (p‐eNOS) was determined by Western blotting in IMA (n=4) simulated by 10 μM NE for 15 min followed by incubation for 5 min with 3 μM CIL or 50 nM bradykinin. The CIL‐induced relaxation was examined in endothelium‐denuded (n=7) and ‐intact IMA (n=7) pretreated with/without LNNA (300 μM, n=8) and ODQ (3 μM, n=8). CIL 3 μM increased eNOS mRNA expression by 42.4% and p‐eNOS by 55.0% in the NE‐stimulated IMA. Endotheliumdenudation (47.7 ± 7.0%, p < 0.05), L‐NNA (48.6 ± 6.1%, p < 0.05), and ODQ (41.6 ± 3.8%, p< 0.01) remarkably reduced the CIL‐induced relaxation to 40 mM K+‐induced contraction, comparing to endothelium‐intact control (73.9 ± 6.4 %). Thus, CIL‐induced endothelium‐dependent relaxation in human IMA is mediated by NOcGMP signal pathway with strong molecular evidence.Supported by St. Vincent Foundation, Hong Kong RGC (CUHK4383/03M) & CUHK (4450171, 4450231, 2041305).
Endogenous endothelin modulates arterial responses to vasoconstrictors, nitric oxide and EDHF
Authors: De Mey Jo G. R. , Lemkens Pieter , Hilgers Rob 
Published: June 2021

Blockade of NO synthase is widely used to study endothelium‐dependent vasodilatation and to diagnose endothelial dysfunction, but can also promote production of endothelin‐1 (ET‐1). We tested the hypothesis that endogenous ET‐1 interferes with arterial contractile reactivity. Isolated rat mesenteric resistance arteries with (+E) or without endothelium (−E) were studied in the presence of indomethacin (1 μmol/L). Contractile responses to potassium (K+, 6 – 42 mmol/L) and phenylephrine (PHE, 0.16 – 20 μmol/L) did not differ between +E and −E. Acetylcholine (Ach, 1 μmol/L) caused small and large E‐dependent relaxations in the presence of K+ and PHE, respectively. L‐NAME (i) did not cause contraction, (ii) markedly increased contractile responses to K+ and PHE in +E, but not −E and (iii) abolished Ach‐induced relaxation during K+ but did not significantly affect it during PHE. The ETa‐ and ETb‐receptor antagonist bosentan (10 μmol/L) (i) did not cause contraction, (ii) reduced contractile responses in +E but not −E, (iii) abolished the E‐dependent procontractile effect of L‐NAME and (iv) significantly increased Ach‐induced relaxation during K+ and PHE in the absence and presence of L‐NAME. We conclude that endogenous ET‐1 increases vasoconstriction and inhibits EDHF‐like reactivity, especially during blockade of NO synthesis.Supported by TIPharma contract# T2_108.
Participation of cycooxygenase‐2‐derived products in the development of hypertension in the SHR
Authors: Ibarra Maximiliano , De la Peña‐García Cesar , Gallardo‐Ortiz Itzell , Villalobos‐Molina Rafael , Torres‐Acosta María Fernanda 
Published: June 2021

Several studies have suggested cyclooxygenase‐2 (COX‐2) plays a significant role in the development of renovascular hypertension. Therefore, the present study was designed to examine the effect of celecoxib a selective COX‐2 inhibitor on the development of hypertension in SHR. Four‐weeks‐old male SHR were divided into four groups: a) Control, b) Celecoxib 0.5 mg/kg/day, c) Celecoxib 1 mg/kg/day, and d) Captopril 30 mg/kg/day. SHR were treated by 10 weeks with these inhibitors in the drinking water. Body weight, heart rate (FC) and systolic blood pressure were evaluated. Kidneys were mounted into an isolated organ chamber in order to measure the contractile response to phenylephrine (alpha‐1 adrenoceptor agonist). At the end of the captopril and celecoxib treatment, systolic blood pressure was reduced in SHR treated (control: 169.7 ± 5.12 mm Hg, celecoxib 0.5 mg/kg: 147.9 ± 5.21 mm Hg, celecoxib 1 mg/kg: 138.7 ± 4.91 mm Hg and captopril 117. 22 ± 3.73). The body weight and heart rate were not modified by treatments. The vasoconstrictor renal response to phenylephrine was lower in SHR than WKY rats. Captopril and celecoxib treatments normalized the contractile response to phenylephrine. These results suggest cyclooxigenase‐2‐derived metabolites could be involved in the development of hypertension in the SHR.Supported by PAPIIT IN218406
Resistance to endotoxic shock in mice lacking natriuretic peptide receptor‐A
Authors: Panayiotou Catherine Maria , Stidwill Raymond , Taylor Valerie , Singer Mervyn , Hobbs Adrian J. 
Published: June 2021

Natriuretic peptides (NP) play key roles in cardiovascular homeostasis via guanylyl cyclase‐linked NP receptors (NPR). Plasma NP levels are increased in patients with septic (endotoxic) shock and correlate with the cardiac dysfunction observed. Yet, a definitive role for NP in the pathogenesis of septic shock has not been established. NO production by inducible NO synthase (iNOS) occurs in response to infection and aberrant regulation of iNOS underlies several cardiovascular disorders. Herein, we have used NPR‐A knockout (KO) mice to investigate a potential role for NP in regulating iNOS expression/activity and (cardio)vascular dysfunction during endotoxic shock.In vivo lipopolysaccharide (LPS) administration caused a greater suppression of responses to U46619, ANP, ACh and SPER‐NO in aortae from WT versus NPR‐A KO mice. This differential vascular function was paralleled by reduced iNOS expression (lung: −38.5±6.3%*, aorta: −80.3±10.2%*; *P<0.05 v WT) and activity (plasma [NOx]: WT 597.7±35.0 μM, NPR‐A KO 387.2±22.4* μM). In accord, LPS‐induced hypotension was enhanced in WT versus NPR‐A KO mice (δmax MABP: WT − 29.7±3.8 mmHg, KO −10.5±6.3 mmHg*).Thus, NPR‐A activation is an important determinant of iNOS expression and (cardio)vascular dysfunction during endotoxic shock and the NP system may represent a novel target in the treatment of this life‐threatening condition.Supported by the Wellcome Trust
Flecainide, but not Ranolazine, Causes Use‐ and State‐dependent Slowing of Ventricular Conduction in Female Rabbit Hearts
Authors: Wu Lin , Li Hong , Rajamani Sridharan , Shryock John C. , Belardinelli Luiz 
Published: June 2021

Background: Flecainide (Flec), an open state Na+ channel (NaCh) blocker, increases the QRS interval and mortality in post‐myocardial infarction patients. Ranolazine (Ran) interacts with the inactivated state of NaCh. This study compares the effects of Flec and Ran on the QRS interval of female rabbit isolated hearts paced at various rates and perfused with 4 mM and8 mM potassium solutions to mimic conditions whereby myocardium is depolarized.Methods: Hearts were instrumented for recording of 12‐lead ECG and paced at rates of 1, 3 and 4 Hz after blockade of AV nodal conduction by thermoablation.Results: Flec (0.1–30 μM, Fig A) and Ran (10–600 μM, Fig B) rate‐ and concentration‐dependently increased the QRS interval. Increases of K+ from 4 to 8 mM and rate of pacing augumented the effect of 2 μM Flec to increase the QRS interval, whereas 10 μM Ran did not increase the QRS interval under any condition tested (Table).Conclusion: Compared to Flec, Ran, at therapeutic concentrations, did not prolong the QRS interval and thereby it should not slow ventricular conduction.
Human MRP2 polymorphisms and their impact on substrate transport
Authors: Megaraj Vandana , Gerk Philip , Kim Richard , Vore Mary 
Published: June 2021

Multidrug resistance protein 2 (MRP2/ABCC2) mediates the biliary excretion of endo‐ and xenobiotic organic anion conjugates. Single nucleotide polymorphisms (SNPs) in the MRP2 gene contribute to variability in drug response and adverse effects between individuals and different ethnic populations. We characterized the transport of wild type MRP2 (WT) and two MRP2 SNP variants, M4 (A1450T) and M5 (V417I) for the substrates LTC4 (leukotrieneC4), E23G (estradiol‐3‐glucuronide), TUDC (tauroursodeoxycholic acid) and E217G (estradiol‐17β‐lucuronide)Methods: WT, M4 and M5 were expressed in Sf9 insect cells and kinetic parameters (Km, μM; Vmax, pmol/mg−1.min−1; Hill coefficient [HC]) of ATP dependant transport of 3H‐LTC4, 3H‐E23G, 3H‐TUDC and 3H‐E217G determined in Sf9 plasma membrane vesicles. Transport activity of M4 and M5 was normalized to WT protein expression.ResultsConclusionThe SNP in the nucleotide‐binding domain of M4 decreased the Vmax by 50% for LTC4, E23G and TUDC and decreased the HC for TUDC and E217G. The SNP in the transmembrane domain 2 of M5 minimally influenced the Vmax, but increased the Km 2–3 fold, increased the HC for TUDC and decreased the HC for E217G. (HD 58299)