bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective correlation of nAChRs and DAT
Authors: Dávila-García Martha Isabel , Gondre-Lewis Marjorie , Hong Wang , Ogunjirin Adebowale E. 
Published: June 2021

Nicotine has been shown to regulate the dopamine transporter (DAT) in a tissue dependent manner and to affect increase both the function of DAT as well as its surface expression (Middleton et al., 2004; Zhu et al., 2009). Here we have looked for a correlation in DAT distribution with sites rich in nAChRS. The binding of DAT was determined using [125I]RTI‐121 and was compared to that of [125I]EB and [125I]α‐BTX in rat brain using receptor autoradiography. Our preliminary results showed a high level of correlation between DAT to non‐α7 nAChRs primarily in mesolimbic and mesocortical areas, but not so in nigrostriatal areas. In the mesocortical and mesolimbic pathways, there were relatively high levels of non‐α7 nAChRs in habenula, nucleus accumbens, prefrontal cortex and cingulated cortex, but only low levels in the olfactory tubercle, hippocampus or in the VTA. There was little or no correlation between DAT and α7 nAChRs. Only modest levels of α7 nAChRs were found in the hippocampus, mammilary bodies, superior colliculus, lateral hypothalamus and entorhinal cortex, and non where found in substantia nigra, VTA, lateral caudate, or olfactory tubercle, areas rich in DAT. Since new studies have found that increase dopamine release is involved with changes in the level of clearance of DA it is important that we further characterize the nAChRs subtype involved in this regulation. The fact that α7‐containing receptors do not correlate to the distribution of DAT will help narrow future studies to the high affinity receptors.This research was supported by NIH R24 MH067627‐01A to MDG Project 2.
NO‐dependent vasodilation is coupled to coordinated activation of connexin‐ and pannexin‐based hemichannels in endothelial cells
Authors: Lillo Mauricio , Gaete Pablo , Saez Juan Carlos , Figueroa Xavier 
Published: June 2021

Nitric oxide(NO)activates connexin(Cx)‐based channels by S‐nitrosylation, but its effect on pannexin(Panx)channels has not been determined. We evaluated the involment of Cx‐and Panx‐based hemichannels in the endothelium‐mediated NO‐dependent vasodilation induced by acetylcholine (ACh) in rat arterial mesenteric bed of rat. Hemichannel activity was assessed by ethidium (Etd) or Lucifer Yellow(LY)uptake. Vessels did not show Etd uptake in control conditions. ACh stimulation induced a strong increase in Etd and LY uptake that was blocked by the Panx blockers probenecid and Panx10, and also carbenoxolone, but only attenuated by La3+ (Cx hemichannels blocker) and 18‐beta‐glycyrrhetinic acid. In addition, Etd uptake was also blocked by the inhibition of NO synthase with NG‐nitro‐L‐arginine (L‐NA), guanylate cyclase soluble with ODQ and PKG with KT5823. The same results were observed with the NO donor S‐nitroso‐N‐acetyl‐ D‐penicillamine (SNAP). However, the increase in Etd uptake activated by the analogue of cGMP, 8‐Br‐cGMP, was only sensitive to probenecid and KT5823, but not to La3+. Interestingly, probenecid potentiated the NO‐dependent, ACh‐induced vasodilation. These results indicate that Cx‐based hemichannels are activated directly by NO, whereas the cGMP/PKG pathway induced the opening of Panx‐formed hemichannels.FONDECYT 1100850, 1090757, 1111033, Anillos ACT‐71
Numerical simulation of blood flow with different red blood cell deformability
Authors: Ju Meongkeun , Low Hong Tong , Kim Sangho 
Published: June 2021

The present study investigated the effect of changes of red blood cell deformability on micro‐hemodynamics by using the Lattice Boltzmann Method (LBM) with Immersed Boundary Method (IBM). The blood flow of 40% stiff red blood cells and 60% normal cells was simulated and the result was compared with that of 100% normal red blood cells. The deformability of stiff cells was 50% less than normal cells. Thus, with the stiff cells, the averaged red blood cell deformability became 20% less than normal condition, which is similar to the condition of malaria‐infected blood. The simulation was conducted at 40% hematocrit and 100 s−1 pseudo shear rate. In this study, the viscosity difference between inside and outside fluids of red blood cell membrane was considered by using a flood fill method. The results showed that the effective viscosity of blood flow with stiff red blood cells significantly increased compared with that without the stiff cells. The axial migration of the stiff cells moving away from the centerline was observed during the simulation.This work was supported by NUS URC Grant R‐397‐000‐091‐112.
Diabetes mellitus modifies endothelial SERCA activity producing a prostaglandin dependent vascular hypercontractility
Authors: Morales-Loredo Juan Humberto , Espinosa-Tanguma Ricardo 
Published: June 2021

To assess the underlying mechanism of diabetes mellitus (DM)‐induced vascular hypercontractility, we evaluated the participation of the sarcoendoplasmic reticulum calcium ATPase (SERCA), the protein kinase C (PKC) and prostaglandins during the contraction induced by phenylephrine (PE) of aorta rings from a 10 weeks streptozotocin (STZ)‐induced DM rat model.PE produced a stronger contraction of DM aorta rings with endothelium vs control (CTRL), (Emax: DM .69 ± .06 vs CTRL .38 ± .07 g. p<0.02). This vascular hypercontractility was eliminated by: a) indomethacin (10μM) pretreatment (Emax: DM .64 ± .07 vs CTRL .55 ± .11 g. ns), and b) endothelium removal (Emax: DM 1 ± .07 vs CTRL .93 ± .04 g., ns). On the other hand, Gö6976 (1μM), a PKC inhibitor, decreased the contractile response in CTRL more than in DM (Emax: DM .55 ± .06 vs CTRL .28 ± .04 g., p<0.01). Also, 1μM thapsigargin (T), a SERCA blocker, increased the CTRL concentration dependent contraction (Emax: CTRL .40 ± .08 vs CTRL+T .76 ± .09, p<0.001), but was not different in DM rings (Emax: DM .66 ± .10 vs DM+T .69 ± .06 g., ns), nor between groups (Emax DM+T .69 ± .07 vs CTRL+T .76 ± .08 g., ns).ConclusionsDuring STZ‐induced DM, endothelial cells release a contractile prostaglandin, perhaps TXA2, that induces vascular hypercontractility.Supported by: P/PIFI‐2010‐24MSU0011E‐13.
Na‐K‐ATPase isoform profile in acquired and genetic forms of hypertension favors the hypertensive phenotype
Authors: Pulgar Victor M , Rashad Hanadi M , Jeffers Anne B , Dickenson Samantha-Rae , Diz Debra I , Aileru Azeez A 
Published: June 2021

The Na‐K ATPase (NK) isoform alpha 2 (α2) contributes to stress‐induced hypertension. We hypothesize that alterations in NK expression and activity contribute to the ouabain‐induced and transgenic (mRen2)27 hypertension. Sprague‐Dawley rats were implanted subcutaneously with a 60‐day 1.5 mg ouabain (OUA) pellet (n = 6 control, n = 6 treated). Blood pressure (BP) was recorded daily via tail cuff for 8 weeks. OUA increased systolic BP by 30% (p<0.05) whereas age‐matched (mRen‐2)27 rats had a 55% higher BP vs control (p<0.05). Expression of the cardiac α2 NK isoform was higher in OUA and (mRen‐2)27 rats (n = 6) vs control (p<0.05), whereas renal NK α1 expression was lower in hypertensive animals (p<0.05). Functional NK activity was analyzed as the relaxation to low KCl concentrations in pre‐constricted renal and mesenteric arteries in K+‐free media and expressed as the difference of area under the curve (dAUC%). NK activity was lower in hypertensive animals in renal [OUA 30 ± 9% vs control 56 ± 6%, p<0.05] and mesenteric vasculature [(mRen‐ 2)27 59 ± 2%; OUA 63 ± 2% vs control 73 ± 3%, p<0.05]. Greater cardiac contractility due to increased NK α2 and increased peripheral vascular tone due to lower functional NK activity would favor hypertension and may be consistent with a contribution of the NK to these two forms of hypertension with known activation of the sympathetic nervous system.NIMHD MD 002303 and NIGMS 5T34GM070416
Autonomic function decline observed in hypoglycemia is attenuated during hyperoxia: potential role of carotid bodies in mediating cardio‐vagal activity
Authors: Taylor Jennifer Lynne , Wehrwein Erica A , Curry Timothy B , Basu Rita , Basu Ananda , Joyner Michael J 
Published: June 2021

Cardio‐vagal tone (CVT) and heart rate variability (HRV) are reduced during hypoglycemia. Carotid body (CB) peripheral chemoreceptors are multi‐modal; therefore we hypothesized a correlation between CB activity and CVT during hypoglycemia. Seven healthy adults (4M/3F) underwent two 180 min hyperinsulemic (2mU/kg FFM/min), hypoglycemic (3.33 mmol/L) clamps one week apart, randomized to normoxia (arterial PO2 (PaO2) 111 ± 6.3 mmHg) or hyperoxia (PaO2 345 ± 80.6 mmHg) to desensitize the CB. CVT was assessed via the high frequency (HF) component of HRV from 5 min periods of 5‐lead ECG recording under baseline (euglycemia) and hypoglycemia. HF values decreased significantly from baseline during hypoglycemia, however this reduction was attenuated under hyperoxia (Normoxia (N): −69% vs. Hyperoxia (H): −41%, p=0.04). Heart rate increased significantly during hypoglycemia (N: 59.7 bpm ± 2.4 vs. 71.9 ± 4.0; H: 60.6 bpm ± 1.9 vs. 68.5 ± 3, p<0.001), however, this increase was not different between normoxia and hyperoxia, despite differences in CVT and HRV. These data indicate that the CB chemoreceptors may be partially responsible for the reduction in CVT associated with hypoglycemia, and they provide evidence for a role of the CB chemoreceptors in parasympathetic tone to the heart. Future studies are required to determine whether inhibition of the CB may serve to improve CVT function during hypoglycemia.T32 DK07352, F32 DK84624‐01 A1, CTSA 1 UL 1 RR024150, R01DK 29953
PACAP causes long‐term increases in sympathetic nerve activity and is necessary for the sympathetic response to acute intermittent hypoxia
Authors: Farnham Melissa Mary-Jean , Pilowsky Paul M 
Published: June 2021

Overall objectiveTo determine if the sustained elevation of splanchnic sympathetic nerve activity (sSNA), termed long‐term facilitation (LTF), following acute intermittent hypoxia (AIH) is due to intermittent, release of sympathoexcitatory peptides, such as pituitary adenylate cyclase activating polypeptide (PACAP).MethodsIn urethane‐anaesthetized, artificially ventilated, male rats (n=18 Sprague–Dawley), we investigated the effect of 10, 45s, episodes of 10%O2–90%N2 every 5 min (AIH) on sSNA after intrathecal infusion of 10μl of vehicle, PACAP (300μM) or the PAC1/VPAC2 receptor antagonist, PACAP(6–38) (1mM). In a separate group of rats (n=6) without AIH, 10 doses of PACAP (10μL of 10μM) were given intrathecally every 5 min.ResultsVehicle‐treated rats showed a 31.0±8.1% increase in sSNA 60min after AIH, which doubled to 67.7±14.1% in PACAP treated rats. Infusing the PACAP antagonist PACAP(6–38) prior to AIH abolished sympathetic LTF (0.1±2.7%). The responses were significantly different (P<0.0001; 2‐way ANOVA). Intermittent, sub‐threshold, infusion of PACAP (10×10μM) was as effective as AIH in causing LTF (sSNA increase of 38.±8.0%).ConclusionPACAP, acting via spinal PAC1/VPAC2 receptors, is sufficient to cause sympathetic LTF in the absence of AIH and necessary for the elaboration of sympathetic LTF following AIH. Support provided by Macquarie University, ARC and NHMRC.
The neuroepithelial body microenvironment as vagal mechanotransducer in intrapulmonary airways
Authors: Lembrechts Robrecht , Brouns Inge , Schnorbusch Kathy , Pintelon Isabel , Timmermans Jean-Pierre , Adriaensen Dirk 
Published: June 2021

Mechanical information collected by sensory nerve terminals in the airways is mainly conducted to the CNS by vagal myelinated nerve fibers. A majority of these terminals contacts densely innervated groups of neuroendocrine airway epithelial cells (neuroepithelial bodies; NEBs), prompting us to study the potential role of NEBs as key transducers of mechanical airway stimuli into activation of vagal sensory terminals. Mild hypo‐osmotic stimuli were used to study mechanosensitivity in a mouse lung slice model for live cell imaging (LCI) of NEBs, and evoked a selective Ca2+ rise in NEB cells. Immunofluorescence and LCI showed that TRPC5, a Ca2+ permeable hypo‐osmotically/mechanically gated TRP channel, was expressed on the apical membrane, and functionally involved in the osmomechanical activation and subsequent release of ATP by NEB cells. ATP may then activate ligand gated P2X2/3 ATP receptors expressed by the terminals of myelinated vagal afferents in the NEB microenvironment. These terminals additionally expressed the inhibitory mechanogated K2P channel TRAAK, likely serving a regulatory role in the indirect mechanical activation. The presented study characterized the NEB microenvironment as a functional unit for vagal airway mechanotransduction.Support: IWT fellowship SB/81162 (RL); FWO grants G.0081.08 (DA) and G.0589.11N (DA, JPT); UA grants GOA BOF 2007 (DA) and KP BOF 2006 (IB)
Ascorbic acid attenuates sympathetic activation and endothelial dysfunction induced by short‐term intermittent hypoxia in humans
Authors: Leuenberger Urs A. , Linton-Frazier Latoya , Spilk Samson , Hogeman Cynthia 
Published: June 2021

In healthy humans, short‐term intermittent hypoxia (IH) raises sympathetic nerve activity mirroring the sympathetic activation seen in patients with obstructive sleep apnea. To explore the role of oxidative stress, we measured blood pressure (BP), sympathetic activity (microneurography) and flow‐mediated brachial artery dilation before and following IH (30 episodes, O2 saturation nadir ~82%) with and without the antioxidant ascorbic acid (50 mg/kg iv) in healthy subjects (age 26±1 yrs; n=13). During saline infusion, IH produced a sustained increase in sympathetic activity (pre vs. post 20.0±1.8 vs. 25.2±1.8 bursts/min; P<0.05) and a small rise of mean BP (pre vs. post 86±2 vs. 89±3 mmHg; P<0.05). In contrast, on a separate day during infusion of ascorbic acid, IH did not raise sympathetic activity (pre vs. post 20.2±2.1 vs. 20.5±2.6 bursts/min; P=NS) or BP (pre vs. post 88±2 vs. 89±2 mmHg; P=NS). Moreover, whereas during saline infusion IH reduced flow‐mediated dilation (pre vs. post 6.8±1.3 vs. 3.2±1.6%; P<0.05), with ascorbic acid this effect was not seen (pre vs. post 6.0±1.2 vs. 6.1±1.4%; P=NS, n=8). These data suggest indirectly that oxidative stress may play a role in the sympathetic activation and vascular dysfunction induced by IH.Supported by P01 HL077670 and UL1 RR033184.
Na/Ca exchanger‐1 mediates hypertrophy of cultured neonatal mouse cardiomyocytes in chronic intermittent hypoxia
Authors: Chen Ling , Wu Guizhen , Zhang Jin 
Published: June 2021

Cardiac‐specific Na/Ca exchanger‐1 (NCX1) knockout (KO) mice is resistant to chronic intermittent hypoxia (CIH)‐induced cardiac hypertrophy in vivo (Chen et al. J Appl Physiol 2010; 109:1675). We studied the effect of CIH on NCX protein expression and cell size in primary cultured neonatal cardiomyocytes from either wild type (WT) or KO mice. CIH was produced by introducing mixed gases containing 0% or 21% O2 at a periodicity of 20 and 20 min, which achieved a nadir pO2 10 and peak 120 mmHg at the bottom of culture media. Daily exposure for CIH included 12h CIH, followed by 12h 21% O2. Control cells were cultured only in 21% O2. At the end of 5‐day exposure, WT with CIH had significantly greater NCX protein expression (~60%) and cell cross sectional area (1158 ± 181 vs 856 ± 98 μm2, P < 0.05) compared to WT control. Cell area in KO with CIH was 917 ± 138 μm2, which is significantly smaller than in WT with CIH (P< 0.05), but not significantly different from either WT or KO controls. NCX protein expression was not significantly different between KO groups, which are ~25% of that in WT control.ConclusionNCX1 mediates cell hypertrophy in cultured neonatal cardiomyocytes following CIH exposure.
Altered muscular activation patterns and force feedback after spinal cord injury
Authors: Niazi Irrum Fawad , Nichols T. Richard , Howland Dena. R 
Published: June 2021

One of the major clinical problems associated with spinal cord injury (SCI) is the lack of animal's ability to maintain weight support during standing or walking. We hypothesize that following SCI there is reorganization of the postural limb reflexes driven by stretch and load receptors in addition to loss of excitatory inputs from supraspinal structures to spinal interneurons that could result in altered intermuscular interactions. In control decerebrate animals there is a proximal to distal gradient in the strength of inhibitory force feedback among the limb muscles. We propose that pathways mediating this inhibition may remain inhibitory after spinal hemisection but their strengths may change to a distal to proximal gradient in the animal resulting in a loss of weight support. We also propose that ventral horn pathways are important for regulating the distribution of intermuscular force feedback. To test our hypothesis we are studying two types of SCI, namely dorsal and lateral hemisections, at both acute and chronic time points post‐injury. We measured intermuscular force feedback using combinations of stretches applied to pairs of muscles. Our most recent evidence supports our hypothesis and shows that the intermuscular force feedback is reversed after lateral but not dorsal hemisections.This work is supported by NIH grant HD32571, 1 I01 RX000243‐01A1, State of Florida BSCIRTF
Mobilization of very small embryonic‐like stem cells by G‐CSF in MACO mice
Authors: Zheng Min , Wang Jian 
Published: June 2021

ObjectiveTo investigate the effect of G‐CSF on neural restoration and on mobilization of very small embryonic‐like stem cells(VSEL‐SC) in bone marrow of focal cerebral ischemia mouse.MethodsMCAO model was produced by filament occlusion method. 50¦Ìg/(kg.d) G‐CSF were given by subcutaneous injection for 5 days. Neurological scale was evaluated. The number of VSEL‐SC (CXCR4+Lin‐CD45‐) in peripheral blood was checked by fluorescence‐activated cell sorting analysis (FACS). Level of stromal derived factor‐1(SDF‐1) in plasma and infarct cerebral tissue were checked by ELISA. Expression of SDF‐1 in ischemia area was checked by immunohistochemical staining.ResultsG‐CSF treatment significantly decreased the neurological scale of MCAO model mice compared with controls. G‐CSF could mobilize VSEL‐SC in the bone marrow of focal cerebral ischemia mice into peripheral blood. The concentration of SDF‐1 in plasma and in cerebral tissue significantly increased in G‐CSF treated group. Expression of SDF‐1 in infarct region significantly increased in G‐CSF treated group.ConclusionThe beneficial effect of G‐CSF may be related to the mobilization of VSEL‐SC and the promotion of SDF‐1 expression in the infarct tissue of MACO mice.This work was supported by National Scientific Foundation Committee of China ( 31100985)
Characterization of hepatocyte‐specific SRSF1 (SF2/ASF) knockout mice
Authors: Langiewicz Magda , Sen Supriya , Webster Nicholas J 
Published: June 2021

Alternative splicing is widely believed to have a major impact on almost all biological processes since it increases proteome complexity and thereby controls protein function. SRSF1 (SF2/ASF) is a member of the SR protein family, which are essential for constitutive splicing and fulfilling regulatory functions in alternative splicing. Previously, we have shown that SRSF1 binds to the alternatively spliced exon 11 of the insulin receptor (INSR) and promotes its incorporation in hepatoma cells. To demonstrate the physiological importance of alternative splicing to the regulation of metabolism, we created a hepatocyte‐specific knockout of SRSF1 (SRSF1LKO) by crossing SRSF1 flox/flox mice with albumin‐cre mice, which specifically express the cre recombinase in adult hepatocytes. Mice are born in the expected mendelian ratio and do not show any growth retardation unlike the hepatocytes specific SRSF3 knockout that we have previously characterized. We will present data showing efficient tissue specific deletion of the SRSF1 allele, the reduction in SRSF1 expression, and alterations in INSR splicing. We will also present data on the metabolic and physiological parameters and liver morphology between SFSR1LKO and littermate control mice, as well as alterations in global gene expression and splicing by exon array analysis. SFSR1LKO is an important model to study alternative splicing in vivo.Supported by a Merit Review Award from the Department of Veterans Affairs.
The effects of betaine supplementation on Pcyt2 +/− (ETKO) mice
Authors: Sivanesan Sugas , Bakovic Marica 
Published: June 2021

The effect of choline metabolite betaine on alleviation of metabolic syndrome phenotype was investigated in CTP: phosphoethanolamine cytidylyltransferase knockout mice (ETKO). Adult ETKO gradually develop liver steatosis, obesity, hyperlipidemia, and insulin resistance even on a chow diet. Obese ETKO and lean 34‐week old wild‐type littermates (WT) were subjected to normal chow diet and supplemented with or without 1% betaine in drinking water for 8 weeks. The food and water intake along with total body weight were continuously monitored and the plasma and tissues lipid content, adipocyte size and liver steatosis were investigated at the end of the treatment. In 8 weeks, untreated ETKO and WT similarly gained 9.7%–10.4% of their initial body weight. Betaine treated ETKO however lost 4.2% of total body weight and there was no betaine effect on WT littermate weight. Treated ETKO plasma triglycerides (TAG) were reduced 40.9% and liver diacylglycerol (DAG) and TAG were reduced by 50% and 37.4% respectively. Significant reductions in adipocyte size and lipid droplet content in treated ETKO livers were histologically observed. The ETKO genes involved in liver lipogenesis including sterol regulatory element binding protein‐1 (SREBP‐1c), fatty acid synthase (FAS), stearoyl‐CoA desaturase (SCD‐1), diglyceride acyltransferase‐1 (DGAT‐1) and diglyceride acyltransferase‐2 (DGAT‐2), had significantly reduced levels of expression after betaine treatments. Mitochondrial genes for fatty acid oxidation such as peroxisome proliferator‐activated receptor alpha (PPARα) and peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α), were on the other hand up‐regulated in comparison to betaine untreated ETKO. The data demonstrates a positive effect of betaine in improving negative effects of obesity and on overall lipid metabolism and mitochondrial function.Grant Funding Source : Ontario Ministry of Agriculture, Food, and Rural affairs
Inhibition of HIV protease inhibitor‐induced inflammatory response and ER stress by raltegravir in macrophages
Authors: Zhao Renping , Zhang Xiaoxuan , Cao Risheng , Hylemon Phillip B , Pandak William M , Zhang Luyong , Wang Guangji , Zhou Huiping 
Published: June 2021

Our previous studies suggest that the HIV protease inhibitor (PI)‐induced ER stress and inflammatory response in macrophages represents an important cellular mechanism of highly active anti‐retroviral therapy (HAART)‐induced dyslipidemia and atherosclerosis. Raltegravir is the first member of the newest class of anti‐HIV drugs, HIV integrase inhibitor. Our recent studies indicate that raltegravir has less hepatic toxicity and could prevent HIV PI‐induced dysregulation of lipid metabolism by inhibiting ER stress in hepatocytes. However, whether raltegravir is also able to prevent HIV PI‐induced inflammatory response, ER stress and lipid accumulation in macrophages remains unclear and is the focus of this study.MethodsJ774A.1 mouse macrophages and human THP‐1‐derived macrophages were treated with HIV PIs (lopinavir/ritonavir) with or without raltegravir. The mRNA and protein levels of TNF‐α and IL‐6 were measured by real‐time RT‐PCR and ELISA, respectively. Activation of ER stress was detected by real‐time RT‐PCR and Western blot analysis. Intracellular lipid was detected using oil‐red O staining.ResultsRaltegravir not only significantly inhibited HIV PI‐induced TNF‐α and IL‐6 expression and ER stress activation, but also reduced HIV PI‐induced foaming cell formation.ConclusionsIncorporation of raltegravir in HAART may reduce HIV PI‐PI‐induced dyslipidemia and atherosclerosis.