bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Exercise Ancestry on Multiple Generations of Mature C57BL/6 Mouse Offspring
Authors: Guth Lisa M , Venezia Andrew C , Marini Michael P , Beltran Estefan P , Spangenburg Espen E , Roth Stephen M 
Published: June 2021

The objective was to examine if exercise (EX) ancestry vs. sedentary (SED) ancestry alters body/tissue mass, glucose metabolism, or muscle mRNA in two generations of mature mouse offspring. C57BL/6 mice (F0) were exposed to EX (wheel running, N=20) or a SED condition (no wheel, N=20) for 12 weeks before breeding. EX males bred with EX females and SED males bred with SED females to obtain F1 pups. F0 EX animals had wheel access through weaning. F1 pups bred with like‐ancestry F1 offspring to obtain the F2 pups. F1 and F2 offspring were sacrificed at 28 wk without EX exposure. Body and tissue masses were recorded, intraperitoneal glucose tolerance was measured, and mRNA expression of several metabolic genes was examined in muscle. In F1 males, liver and soleus mass were lower in EX (p < 0.05). F2 EX males also had lower liver and soleus masses (p < 0.05). In females, no differences in tissue mass were observed. However, F1 EX females had higher baseline glucose (p < 0.05) while F2 SED females had better glucose tolerance (p < 0.05). No differences in glucose or glucose tolerance were observed in male offspring. Pgc1a mRNA expression was higher in F1 EX males and Cox1 mRNA expression was higher in F2 SED males. There were no other differences in mRNA expression. These findings suggest limited, generation‐ and sex‐specific effects of EX ancestry on tissue mass, glucose metabolism, and muscle mRNA in two generations of mature C57BL/6 offspring.This work was supported by NIH grants HD062868 and AG000268.
Beneficial effect of exercise combined with licorice flavonoid oil supplementation on visceral adipose tissue
Authors: Tanaka Masayuki , Kanazashi Miho , Tanaka Minoru , Kondo Hiroyo , Murakami Shinichiro , Fujita Naoto , Fujino Hidemi 
Published: June 2021

ObjectiveWe investigated the beneficial effect of exercise combined with licorice flavonoid oil (LFO) on visceral adipose tissue, and the lipid metabolism in skeletal muscle and liver.MethodsMale Sprague‐Dawley rats divided into four groups: control, exercise, control with LFO, and exercise with LFO groups. The rats subjected to exercise ran on a treadmill 5 times a week. LFO was administered 1500mg/kg body weight daily. After 7 weeks, overnight fasted rats were killed, and samples were collected. Adipocyte cell size in the epididymal white adipose tissue and the fat‐oxidation related enzyme, CS, HAD and CPT‐2, activities in the plantaris muscle and liver were measured.ResultsBoth exercise and LFO reduced the adipose tissue mass and adipocyte cell size. In addition, exercise combined with LFO more effectively reduced the adipose tissue than only exercise or LFO. Furthermore, exercise increased the muscular CS and HAD activities, and LFO increased the hepatic CPT‐2 activity.ConclusionExercise combined with LFO effectively reduced visceral adipose tissue, because the combination enhanced the muscular and hepatic lipid metabolism, respectively. These results suggested that the combination might be effective to decrease the risk from obesity. Supported by Grants‐in‐Aid for Science Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
R‐type Ca2+ Channels Contribute to Neural Control of Murine Colonic Motility
Authors: Skylis Laura , Galligan James , Rodriguez‐Tapia Eileen 
Published: June 2021

BackgroundThe enteric nervous system controls gastrointestinal motility. Multiple subtypes of voltage‐gated Ca2+channels contribute to neurotransmitter release from enteric neurons.ObjectiveWe tested the hypothesis that R‐type Ca2+channels contribute to enteric neurotransmitter release in the mouse colon.MethodsStudies were done in vivo and in vitro using wild type (WT) and a1E Ca2+ channel (R‐type) knockout (KO) mice. Fecal output was measured in vivo. The colonic migrating motor complex (CMMC) was measured in vitro. We used NiCl2 (50 mM) to block R‐type Ca2+ channels , Ω‐conotoxin (CTX, 0.1 mM) to block N‐type Ca2+ channels and tetrodotoxin (TTX, Na+ channel blocker, 0.3 mM) on CMMCs.ResultsThere was no significant difference in fecal output between a1E KO and WT mice. There was no difference in the frequency, propagation speed or amplitude of CMMC contractions between colons from WT and a1E KO mice. NiCl2 slightly decreased contraction amplitude in colons from a1E KO and WT mice. CTX and TTX completely blocked neurogenic contractions and disrupted the CMMC pattern, leaving only spontaneous myogenic contractions behind.ConclusionThese results suggest that either R‐type Ca2+ channels have a minor role in controlling colonic motility, or that there is compensatory upregulation of other Ca2+ types in the constitutive a1E KO mice.*Supported by: R01DK094932
Regeneration associated pathophysiology following major hepatectomy with subsequent choledoco‐jejunostomy: A comparison with simple hepatectomy
Authors: Takagi Takehiro , Yokoyama Yukihiro , Kokuryo Toshio , Yamaguchi Jumpei , Nagino Masato 
Published: June 2021

BackgroundThe hepatectomy with extrahepatic bile duct resection and subsequent choledoco‐jejunostomy (CJ) are often required in bile duct carcinoma. However, the impact of CJ is unknown in the liver regeneration after major hepatectomy.MethodsWe established a novel rat model, 70% hepatectomy with CJ (Hx+CJ rat). The inflammatory response and regeneration rates were evaluated in the liver using 70% hepatectomy (Hx rat) or hepatectomy with CJ (Hx+CJ rat). The gene expression was analyzed concerning inflammation and regeneration in the liver of these two groups.ResultsHistological examination revealed that progressive periportal inflammatory response in the liver of Hx+CJ rat. The hepatic regeneration rate was significantly lower in the Hx+CJ rat compared to the Hx rat on days 2 and 4 after surgery. The expression of inflammation‐associated genes was higher in the liver of the Hx+CJ rat than the Hx rat. The regeneration‐associated genes, such as hepatocyte growth factor and epidermal growth factor were significantly lower in the Hx+CJ rat than the Hx rat.ConclusionThese results showed that CJ impairs the liver regeneration after major hepatectomy. CJ induce the progressive periportal inflammation in the liver. The inflammation partly causes the suppression of regeneration‐associated genes in the liver.
Breathing Frequency (fR) Is No Longer Under Chemoreflex Control During REM Sleep
Authors: Burke Peter , Kanbar Roy , Basting Tyler , Viar Kenneth , Stornetta Ruth , Guyenet Patrice 
Published: June 2021

ObjectiveTo define the contribution of central chemoreception in general and the retrotrapezoid nucleus (RTN) in particular to the regulation of breathing in REM sleep.
MethodsEEG, neck EMG, blood pressure, fR and tidal volume (VT) were recorded in 23 conscious adult male Sprague‐Dawley rats. RTN was optogenetically stimulated with channelrhodopsin‐2 (ChR2, 20s) or inhibited with archaerhodopsin (Arch; 10 s) during natural sleep and quiet wake periods. ChR2 and Arch were delivered using previously described PRSX8‐promoter containing lentiviral vectors.
Main ResultsIn quiet wake or non‐REM sleep, hypercapnia (3 or 6% FiCO2) increased both fR and VT; in REM sleep, hypercapnia increased VT but fR was unaffected. Optogenetic inhibition of RTN neurons reduced VT in all three states but reduced fR only during quiet wake and non‐REM sleep. Optogenetic stimulation of RTN neurons always increased VT but raised fR only in quiet wake and non‐REM sleep. Phasic stimulation of RTN at frequencies above resting fR entrained and shortened the breathing cycle except in REM sleep. Phasic RTN stimulation produced active expiration only during wake and increased fR exclusively by reducing the duration of the post‐inspiratory phase.ConclusionsDuring REM sleep, VT regulation by both hypercarbia and RTN is retained but the overall hypercapnic ventilatory reflex is reduced because fR is no longer under chemoreceptor control. Furthermore, respiratory drive contributed by RTN is remarkably state‐dependent, active expiration being elicited only during wake and tachypnea only during non‐REM sleep and quiet wake. Support: HL074011.
NMDA receptors and Nitric Oxide Synthase Regulate Encoding of Cough in the nTS
Authors: Farmer David , Mori Nanako , Canning Brendan 
Published: June 2021

We sought to locate and characterize the central terminations of cough receptor airway afferents in the nucleus tractus solitarii (nTS) of guinea pigs. Neuronal tracing indicated that cough receptors terminate in locations bordering the medial and intermediate nTS. Microinjection of NMDA receptor antagonists into these locations nearly abolished cough evoked by citric acid (0.001‐2M; 100μl aliquots) applied to the trachea of anaesthetised animals (vehicle: 10±3; AP‐5: 3±2; SDZ 220‐581: 0±0 coughs; n=3‐6).Microinjection of NMDA produced respiratory perturbations including tachypnoea (0.01nmol NMDA) and bradypnoea/apnoea (0.1nmol NMDA) that were eliminated by NMDA receptor antagonists or inhibitors of nitric oxide synthase (NOS): L‐NNA (non‐specific) or N‐propyl‐L‐arginine (NPLA) (neuronal NOS‐specific). NOS inhibitors also reduced citric acid‐evoked coughing (Vehicle: 11±2; L‐NNA: 4±1; NPLA 4±2 coughs; n=6‐8). Citric acid‐induced cough was not attenuated after inhibition of soluble guanylate cyclase (sGC) with ODQ (vehicle: 11±3 coughs; ODQ: 14±2 coughs; n=8) or potentiated after inhibition of phosphodiesterase‐5 (PDE5) with zaprinast (vehicle: 9±3 coughs; zaprinast 10±1 coughs; n=3). Our data indicates that reflex cough is dependent on NMDA receptor activation and/or NO in the nTS. NO signalling occurs independent of either sGC or PDE5, suggesting that alternative signalling mechanisms are at play.Work supported by NIH.
Mechanism of impaired lipid homeostasis in MCPIP1‐deficienct mice
Authors: Sedinkin Jessica , Chang Yingzi 
Published: June 2021

BackgroundMonocyte chemotactic protein‐induced protein 1 (MCPIP1) is found in monocytes/macrophages in response to MCP‐1 stimulation. Our preliminary data showed that MCPIP1 knockout mice have increased plasma LDL cholesterol and decreased HDL and total triglycerides. We have also found that mice lacking MCPIP1 display a marked loss of adipose and muscle tissues. Our current project was designed to determine whether MCPIP1‐deficiency impairs lipid homeostasis by affecting the apoprotein expression hepatic remodeling.MethodsC57/BL6 mice at 6‐8 weeks of age were used. Liver histological changes and plasma apoprotein expression were examined in samples collected from wild‐type, heterozygous, and MCPIP1 knockout mice.Resultshepatic histological staining revealed an increase in collagen and fibrous tissue and a decrease in hepatocytes in MCPIP1 knockout mice. We also found that the expression of LPL, and apoB48 is increased but the apoB100 and apoA‐1 is decreased in the plasma from MCPIP1 knockout mice.ConclusionsThe data collected so far suggest that the impaired lipid homeostasis observed in MCPIP1 deficient mice may occur through hepatic remodeling and alteration of apoprotein expression and/or function.
How Physically Active are Statin Users? The Polish Norwegian Study (PONS)
Authors: Vansal Sandeep , Vaidean Georgeta , Manczuk Marta 
Published: June 2021

IntroductionPharmacological treatment of hypercholesterolemia needs to be accompanied by increased physical activity. Whether this is implemented is not fully known.MethodsWe used cross‐sectional data of 12754 participants, ages 45 to 64 years, in an ongoing cohort study in Poland. Statin use during the last 30 days was recorded. Physical activity assessment was based on the validated International Physical Activity Questionnaire. ResultsThere were 1728 (13.55%) statin users. Fewer statin users (37.56%) than non‐users (39.37%) reached the highest physically active category (p < 0.05). Statin users were 1.24 (95% CI: 1.13 to 1.37) more likely to watch TV for more than 20 hours/week (29.72%) than non‐statin users (23.10%) , even when age, gender, BMI, muscle/joint pain and cardiovascular disease status were adjusted for. The proportion of people meeting the recommended activity levels of 500‐1000 MET‐minutes/week, minutes spent sitting, engaging in walking activities, moderate and vigorous activities were not statistically significant between statin users and non‐users, adjusting for age and BMI. Statin‐users were more likely to report poor overall health (8.35%), muscle/joint pain (73.96%) and poor health as a barrier to exercise (14.72%) than non‐statin users (4.69%, 66.12% and 8.29% respectively, all p < 0.001).ConclusionStatin‐users do not have more favorable physical activity patterns than non‐users. Further studies are needed to explore the contribution of the “false reassurance” phenomenon and that of medication side effects.
Cadmium Levels in Maternal and Cord Blood and Anthropometric Parameters of Newborns in Nnewi,South‐Eastern Nigeria
Authors: Obi Ejeatuluchukwu , Agbasi Patrick , Orisakwe Orish , Nriagu Jerome 
Published: June 2021

The study investigated the cadmium levels in maternal and cord blood and also tried to find out if there was any correlation between cadmium level and anthropometric parameters in the newborns A total of 119 pregnant women from the third trimester to delivery were recruited from three different hospitals in Nnewi , South Eastern Nigeria. Maternal and umbilical cord blood samples (4ml) were collected at delivery and put into EDTA sample containers and were stored at ‐80C before transporting them to the University of Michigan ,Michigan ,USA for analysis of heavy metals. Cadmium were analyzed in a Class 100 facility using an Agilent 7500c series inductively coupled plasma/mass spectrometer (ICP‐MS) Cadmium was detected in all the maternal and cord blood samples. The mean cadmium level in cord blood was 1.72 x 10‐3 ppm and that of the maternal blood was1.73 x 10‐3 ppm.The prevalence of abnormal cadmium level in mothers' blood is 73.1% and that of the cord blood was 68.9%.The anthropometric measurements showed that mothers whose blood had abnormal cadmium level delivered newborns with significantly lower (P<0.05) body weight and length compared to those with normal cadmium level. This study reveals the presence of cadmium in both maternal and cord blood more than the permissible cadmium level and this calls for a great concern because of its inherent health implications.
Effect of L‐cysteine on Glutamate‐Induced Excitotoxicity in Bovine Neural Retina
Authors: Mitchell Leah , Fasiku Oluwaseyi , Robinson Jenaye , Opere Catherine , Ohia Sunny , Njie‐Mbye Ya Fatou 
Published: June 2021

Excessive glutamate production in the retina has been implicated in some ocular neurodegenerative diseases. There is evidence that hydrogen sulfide (H2S) can exert neuroprotective action against damage induced by oxidative stress or excitotoxicity in the central nervous system.PurposeTo investigate the pharmacological effects of L‐cysteine, a substrate for H2S biosynthesis, on glutamate‐induced excitotoxicity in bovine neural retina.MethodsIsolated bovine neural retinae were pretreated with L‐cysteine (10 nM ‐ 1 µM) prior to insult with 2mM glutamate, and retinal neuron survival was assessed using the methylthiazolydiphenyl‐tetrazolium bromide (MTT) assay. For studies aimed at determining the involvement of the H2S biosynthesis pathway, glutamate‐induced neurotoxic retinas were pretreated with enzyme inhibitors for H2S biosynthesis [aminooxyacetic acid (AOA, 30 µM), DL‐propargylglycine (PAG, 1mM), and ketobutyric acid (KBA, 1mM)], prior to L‐cysteine (100 nM) treatment.ResultsIn the presence of glutamate (2 mM), only 68% of neurons survived when compared to control. The H2S substrate, L‐cysteine (100 nM) significantly (P<0.001) reversed glutamate (2 mM)‐induced neuron degeneration by 32%. Interestingly, the H2S biosynthetic enzyme inhibitors, AOA, PAG, and KBA did not alter the neuroprotective effects of L‐cysteine.ConclusionL‐cysteine can protect bovine neural retina from glutamate‐induced excitotoxic damage. However, the neuroprotective effect of L‐cysteine does not involve de novo intramural biosynthesis of H2S.
Calibration of an in‐silico Human Ventricular Action Potential Model to Detect Proarrhythmic Liabilities
Authors: Green Jonathon , Sutherland J , Gintant Gary 
Published: June 2021

In‐silico models of human ventricular action potentials (APs) are useful for defining the roles of specific ionic currents on cardiac repolarization and integrating drug effects on multiple cardiac ionic currents. To provide utility in defining proarrhythmic risk, these models need to be adequately benchmarked regarding their ability to generate cellular proarrhythmia. The present studies calibrated the proarrhythmic liabilities of blocking single and multiple ionic currents using ventricular APs from the O'Hara‐Rudy (ORd) model based on delayed repolarization and early afterdepolarization (EAD) activity.An endocardial cell model paced at a cycle length (CL) of 4 sec was used to reconstruct AP changes; the maximal conductance of IKr (hERG current), along with IKs, ICaL, INaL, and Na/K pump current were reduced (both individually and in concert with IKr).Decreasing IKr conductance caused AP prolongation and typically required 150‐250+ beats to reach steady‐state responses when no EADs were present. EADs were first observed when IKr was reduced by 85%; additional IKr block yielded APs with patterns of 1‐6+ EADs. When concurrently blocking IKr, EADs were less prevalent when inward currents (either ICaL or INaL) were reduced, and more prominent when outward currents (either NA/K pump or IKs) were reduced.In conclusion, in the ORd model, a) EAD activity is typically oscillatory (even after several minutes of simulated pacing), often with no stabilized, steady state rate or pattern, b) EAD activity is present only with substantial IKr block, is reduced with concomitant block of inward ICaL and INaL, and is increased by reducing IKs or Na/K pump current.This research was supported by AbbVie.
PARP Inhibition Blocks Asthma Manifestation in a Chronic House Dust Mite (HDM) Asthma Model and Differentially Modulates Human CD4+T cell Function
Authors: Ghonim Mohamed , Naura Amarjit , Pyakurel Kusma , Lammi Matthew , Rodriguez Paulo , Ibba Salomi , Al‐Khami Amir , El‐Bahrawy Ali , Rady Hamada , Zea Arnold , Mansy Moselhy , Ochoa Augusto , Boulares Hamid 
Published: June 2021

One of the most essential goals for treatment of allergic asthma is the identification of therapeutic drugs that block the release or effects of Th2 cytokines. Here we show that PARP is highly activated in lung tissues and PBMCs from asthmatics demonstrating relevance to the human disease. Using HDM‐based chronic model, we show that a single administration of olaparib, a PARP inhibitor, was effective in decreasing lung eosinophilia and overall cellularity. Two additional administrations of the drug provided better protection and significantly reduced airway hyper‐responsiveness. These results were confirmed using similarly exposed PARP‐1−/− mice. Such protective effects may be mediated by a significant reduction in Th2 cytokines and a concomitant increase in T‐regulatory cells. Using human CD4+T cells, we show that PARP inhibition significantly reduced Th2 cytokine production in response to CD3/CD28 stimulation without affecting production of IFN‐γ, T cell proliferation, or the overall numbers of Th1 or Th2 cells. However and similarly to our animal studies, PARP inhibition markedly increased the number of human T‐regulatory cells suggesting that PARP inhibition may not affect Th1/Th2 differentiation but alters their ability to produce Th2 cytokines. Our findings provide additional support to the potential of PARP inhibition as a novel strategy for the treatment of asthma.Source: NIH, ECEB funds
A Simulated Cell Reprogramming from a Pharmacological Perspective
Authors: Nadal‐Quiros Monica , Moore Leon , Marcano Mariano 
Published: June 2021

By means of mathematical models, we propose a strategy for identifying the functional changes required to reprogram one type of cell into another. Here, we focus on altering the activity or expression of key transport proteins rather than manipulation of the cell nucleus or the use of embryonic stem cells. We illustrate this strategy by simulating the reprogramming of a sensory macula densa (MD) cell into a transporting cortical thick ascending limb (cTAL). Models of each of these two renal epithelial cell types were developed, and each contains sub‐models of an array of transport proteins and channels known to be expressed in both cell types although in different quantities. The MD‐to‐cTAL cell reprogramming simulations showed that just increasing (~4‐fold) basolateral Na+/K+ ATPase expression in MD cells and fixing to zero the apical membrane water permeability was sufficient to elicit behaviors exhibited by cTAL cells (low and essentially constant cytosolic [Na+] and cell volume when apical [NaCl] varies). In summary, the MD cell reprogramming only required alteration in less than 20% of the transport processes included in the models. These results illustrate how mathematical models can be used to explore possible pathways for pharmacological and genetic manipulation to functionally transform cells by augmenting or diminishing protein expression or activity without the need of reversing the cell differentiation process.Research supported in part by the NIH MBRS‐RISE Grant 2R25GM061151 and the NIH‐NIGMS Grant SC1GM084744.
Role of PTEN in Hypoxic Pulmonary Vasoconstriction
Authors: Krauszman Adrienn , Kuebler Wolfgang 
Published: June 2021

RationaleHypoxic pulmonary vasoconstriciton optimizes ventilation/perfusion matching in the lung, and critically depends on transient receptor potential canonical (TRPC) 6 activation and trafficking to caveolae. However, underlying regulatory mechanisms are yet unclear. In endothelial cells, phosphatase and tensin homolog (PTEN) has been shown to serve as a scaffold for TRPC6, enabling cell surface expression of the channel and subsequent Ca2+ entry independent of its phosphatase activity. Based on these data we hypothesized that the interaction between PTEN and TRPC6 in PASMC may be required for TRPC6 transloaction to caveolae and an intact HPV response.MethodsInteraction between PTEN and TRPC6 was tested by co‐immunoprecipitation in whole lung lysates, and by proximity ligation assay in pulmonary artery smooth muscle cells (PASMC). Caveolar recruitment of proteins was assessed in PASMC by sucrose density gradient ultracentrifugation. HPV was analyzed in isolated perfused lungs as hypoxia‐induced incresae in perfusion pressure.ResultsHypoxia induced protein‐protein interaction between PTEN and TRPC6 in both whole lungs and PASMC. Hypoxia also translocated PTEN to caveolae (caveolin 1‐rich fraction) but inhibition of ROCK (Y27632; 5 µM) prevented this translocation. HPV response was significantly attenuated by Y27632, yet not by the PTEN phosphatase inhibitor VO‐OHpic (1‐50 µM).ConclusionHypoxia induces PTEN interaction with TRPC6 in PASMC, and PTEN translocation to caveolae in a ROCK‐dependent manner. PTEN may play an important role in TRPC6 recruitment and activation downstream of ROCK and thus, mediate HPV in a manner that is independent of its phosphatase activity.Funded by a CIHR operational grant to WMK.