bluuebunny/crossref_metadata_2025_split huggingface dataset:
Egr‐1 mediates the suppressive effect of IL‐1 on PPARg expression in human OA chondrocytes
Authors: Nebbaki Sarah , El Mansouri Fatima Ezzahra , Zayed Nadia , Benderdour Mohamed , Martel-Pelletier Johanne , Pelletier Jean-Pierre , Fahmi hassan 
Published: June 2021

BackgroundPeroxisome proliferator‐activated receptor gamma (PPARg) is a ligand activated transcription factor. Several lines of evidence indicate that PPARg have protective effects in osteoarthritis (OA). We have previously shown that IL‐1 down‐regulated PPARg expression in OA chondrocytes. In the present study we will investigate the mechanisms underlying this effect of IL‐1.MethodsChondrocytes were stimulated with IL‐1, and the level of PPARg and Egr‐1 protein and mRNA were evaluated using WB and Real Time‐RT‐PCR, respectively. The PPARg promoter activity was analyzed in transient transfection experiments. Egr‐1 recruitment to the PPARg promoter was evaluated using ChIP assays. Small interfering RNA (siRNA) approaches were used to silence Egr‐1 expression.ResultsWe demonstrated that the suppressive effect of IL‐1 on PPARg expression requires de novo protein synthesis. ChIP analyses revealed that IL‐1 induced Egr‐1 recruitment at the PPARg promoter. IL‐1 inhibited the activity of PPARg promoter and overexpression of Egr‐1 potentiated the inhibitory effect of IL‐1, suggesting that Egr‐1 may mediate the suppressive effect of IL‐1. Finally, Egr‐1 silencing with siRNA blocked IL‐1‐mediated down‐regulation of PPARg expression.ConclusionThese results indicate that Egr‐1 contributes to IL‐1‐mediated down‐regulation of PPARg expression in OA chondrocytes.
Transcutaneous Carbon Dioxide Monitoring During Acute Respiratory Distress Syndrome Due to Smoke Inhalation and Burns
Authors: Belenkiy Slava , Ivey Katherine , Batchinsky Andriy , Langer Tom , Necsoiu Corina , Vecchi Vittoria , Baker William , Chung Kevin , Salinas Jose , Cancio Lee 
Published: June 2021

We evaluated the accuracy of continuous noninvasive transcutaneous carbon dioxide (tPCO2) monitoring utilizing the SenTec Digital Monitoring System in a model of ARDS due to smoke inhalation and burns.Subjectsanesthetized female Yorkshire pigs (47.4 ± 0.9 kg) received wood bark smoke inhalation injury and 40% total body surface area full thickness flame burn. A SenTec sensor heated to 43.5°C was used. Correlation of tPCO2 with arterial PaCO2 measured intermittently with i‐STAT blood gas analyzer.Resultsall animals developed ARDS at 23±2.08 hrs. Mean survival time was 51±14.9 hrs. A total of 88 paired measurements of PaCO2 and tPCO2 were performed. The mean overall bias between PaCO2 and tPCO2 under stable conditions (Bland‐Altman analysis (BAa)) was 0.75±5.34 mm Hg with overall correlation (R2 = 0.79, P<0.0001). Eighty‐nine percent of measurements were within the acceptable clinical range of agreement of ± 7.5mm Hg. This relationship deteriorated under hemodynamic instability with overall bias increasing to 17.3±18.5 mm Hg (BAa) and poor correlation (R2= 0.02, P=0.53) and only 33% of measurements were within the acceptable clinical range of agreement.ConclusionsTranscutaneous CO2 monitoring is a reliable surrogate for PaCO2 in the setting of severe lung injury and hemodynamic stability. Additional information must be considered during hemodynamic instability for accurate estimation of PaCO2.
Mean Total Cholesterol/HDL‐Cholesterol Ratio and hs‐CRP Levels Among Foreign‐born Afro Caribbeans and their United States‐born Counterparts in South Florida
Authors: Davis Errol , Huffman Fatma , Dehpahlavan Jaleh 
Published: June 2021

ObjectiveIn a cross‐sectional study we examined total cholesterol/high‐density lipoprotein cholesterol (TC/HDL‐Cholesterol) and high‐sensitivity C‐reactive protein (hs‐CRP) values in 66 Foreign‐born Afro Caribbean (FBAC) living in the US for less than 10 years, 62 US‐born Afro Caribbean American (USBACA) and 61 African American (AA) adults (18–40 years).ResultsThere were no significant statistical differences between the groups with respect to TC, HDL‐Cholesterol or TC/HDL‐Cholesterol ratio. However, the AA participants compared to the FBAC and USBACA participants had significantly (p< 0.01) higher hs‐CRP levels (2.2 ± 2.7 vs. 1.1 ± 1.3 and 1.3 ± 1.6 mg/L). This statistical significant difference was also seen in the female ethnic groups but, not the males. There were no correlation between blood lipids and hs‐CRP, however, there were positive correlation between TC and TC/HDL‐C ratio but, negative correlation between HDL‐C and TC/HDL‐C ratio.ConclusionWe have demonstrated statistical significant differences in hs‐CRP levels between different ethnic subgroups of the same racial group. Understanding the ethnic and cultural differences and the variations in health indicators among different ethnic groups of the same race can help us to develop culturally sensitive programs and strategies for the improvement of health outcomesSource of funding: Florida International University Foundation
Elevated Gluconeogenesis in Aging and Lung Cancer is Related to Inflammation and Blunted Insulin‐Induced Protein Anabolism
Authors: MacAdams Jacqueline , Winter Aaron , Morais José A. , Burgess Shawn C. , Chevalier Stéphanie 
Published: June 2021

Cancer and aging are both accompanied by metabolic alterations leading to muscle loss that may result from an increased use of amino acids for gluconeogenesis (GNG).Methodswe measured the fractional contributions (%) of glycogen, glycerol and GNG from phosphoenolpyruvate (PEP) to 17h‐fasting endogenous glucose production (EGP), using oral 2H20 and deuterium enrichment of plasma glucose, by NMR spectroscopy. Whole‐body protein and glucose kinetics (1‐13C‐leucine and 3H3‐glucose) were measured fasting and during a subsequent hyperinsulinemic, euglycemic, isoaminoacidemic clamp in: young (Y, n=11; 27±3 y), older (O, n=13; 65±2 y) and older men with lung cancer (CA, n=9; 66±2 y).ResultsMen with CA had greater serum CRP levels and resting energy expenditure (REE) than Y and O, and a lesser clamp glucose disposal, indicating insulin resistance. EGP was elevated with aging and cancer with greater contribution from GNG: Y:37±2, O:43±2 and CA:48±4% (ANOVA p<0.05); % contribution from glycogen and glycerol did not differ. The resulting GNG flux (EGP × %GNG) correlated positively with CRP (r=0.69) and REE (r=0.61), and negatively with fat‐free mass index (r=−0.41), all p<0.05. GNG flux was related to lesser glucose uptake and protein anabolic response (r= −0.54, p=0.001) in response to insulin.ConclusionsInflammation may underlie the greater production of glucose from GNG and blunted protein anabolism. (CIHR)
Punishment by intravenous nicotine in rats
Authors: Truong Yen Nhu‐Thi , Woods James 
Published: June 2021

RationaleAlthough it is known that humans will self‐administer intravenous nicotine, the motivational valences of nicotine are not well understood. In order to address the seeming paradox involving the positive and negative subjective effects of nicotine, we have developed operant choice procedures that allow us to detect when intravenous nicotine results in both increases and decreases in behavior resulting in its self‐administration.ObjectiveTo examine the effects of contingent and non‐contingent intravenous nicotine on sucrose‐maintained operant responding.MethodsThe effects of intravenous nicotine on sucrose maintained behavior in a two‐lever operant chamber was measured in rats.ResultsResponse‐contingent nicotine dose‐dependently decreased sucrose maintained‐behavior in our operant choice procedures, and when available, nicotine increased responding maintained by only sucrose alternative consequence. Delay in response‐contingent nicotine attenuated the punishing effect of nicotine. Non‐contingent nicotine, at total cumulative doses equal to and above those self‐administered did not punish sucrose‐maintained behavior.ConclusionIntravenous nicotine may serve as a punisher of sucrose‐maintained behavior in rats. University of Michigan Rackham Merit Fellowship.
Ionotropic but not metabotropic glutamatergic receptors in the Locus Coeruleus modulate the hypercapnic ventilatory response in unanesthetized rats
Authors: Dias Mirela Barros , Taxini Camila L , Puga Cintia C.I. , Gargaglioni Luciane H , Bícego Kênia C. 
Published: June 2021

Central chemoreception is an important mechanism by which changes in tissue CO2/H+ regulate breathing, and the Locus coeruleus (LC) is one of many putative central chemoreceptor sites. Here, we studied the contribution of LC glutamatergic receptors on ventilatory, cardiovascular and thermal responses to hypercapnia. To this end, we measured pulmonary ventilation (VE), body temperatures (Tb), mean arterial pressure (MAP) and heart rate (fH) of male Wistar rats before and after microinjection of Kynurenic Acid (KY, an ionotropic glutamate receptors antagonist, 10 mM) or α‐methyl‐4‐carboxyphenylglycine (MCPG, a metabotropic glutamate receptor antagonist, 10 ηM) unilateraly into the LC, followed by 60 minutes of air or hypercapnia exposure (7% CO2). Ventilatory response to hypercapnia was higher in animals treated with KY intra‐LC (1899 ± 83 mL kg−1 min−1) compared to the control group (1141 ± 64 mL kg−1 min−1; P < 0.01). However, the MCPG treatment within the LC had no effect on the hypercapnia‐induced hyperpnea. The cardiovascular and thermal control were not affected by hypercapnia or by the injection of KY and MCPG in the LC. These data suggest that the glutamate acting on ionotropic but not metabotropic receptors in the LC exerts an inibitory modulation of hypercapnia‐induced hyperpnea.Financial support: FAPESP, CNPq, PROPe.
Inhibition of the receptor of advanced glycation reverses pulmonary arterial hypertension
Authors: Meloche Jolyane , Courchesne Antony , Barrier Marjorie , Tremblay Marie‐Pier , Breuils‐Bonnet Sandra , Tremblay Eve , Provencher Steeve , Bonnet Sebastien 
Published: June 2021

Pulmonary arterial (PA) hypertension (PAH) is a vasculopathy characterized by enhanced PA smooth muscle cells (PASMC) proliferation and suppressed apoptosis. A recent proteomic analysis of PAH lungs demonstrated that the receptor of advanced glycation endproducts (RAGE) is one of the most upregulated proteins in PAH patients. We hypothesized that RAGE could play a critical role in PAH etiology and progression. We demonstrated a specific RAGE overexpression in PAH lungs. In human PASMC, we showed that RAGE was implicated in the proliferative and apoptosis‐resistant phenotype. Recent studies demonstrated an altered BMPR2 (Bone Morphogenetic Protein Receptor 2)/PPARγ (Peroxisome Proliferator‐Activated Receptor gamma) axis in PAH. We showed that RAGE is accountable for BMPR2/PPARγ downregulation, thus regulating proliferation and apoptosis. In vivo, RAGE inhibition (siRNA nebulization) in rats with Sugen‐induced PAH showed decreased PA pressure and right ventricular hypertrophy, associated with a significant improvement in lung perfusion and decreased PA wall thickness. To conclude, we demonstrated the implication of RAGE in PAH etiology. Thus, RAGE inhibitors, which are in clinical phase II for Alzheimer's disease, represent potential therapeutic agents for PAH treatment.A Canadian Thoracic Society scholarship to JM and Canadian Institutes of Health Research grants to SB supported this work.
Activation of calpain in pulmonary arterial smooth muscle cells (PASMCs)
Authors: Kovacs Laszlo , Rafikov Ruslan , Szabo Andras , Bagi Zsolt , Black Stephen M. , Su Yunchao 
Published: June 2021

Pulmonary arterial hypertension (PAH) is a disease characterized by remodeling of vessel walls. Growth factors, inflammatory cytokines, reactive oxygen species (ROS), and calpain contribute to pulmonary vascular remodeling. In the present study, we studied whether calpain is activated by growth factors, inflammatory cytokines, and ROS. Pulmonary arterial smooth muscle cells (PASMCs) were treated with platelet‐derived growth factor‐BB (PDGF‐BB), serotonin (5‐HT), endothelin‐1 (ET‐1), interleukin‐6 (IL‐6) as well as H2O2, and calpain activity was measured using specific fluorescent substrates. Treatment with the stimulators mentioned above caused dramatic increases in calpain activity. The elevated calpain activity correlates with the increases in collagen‐I expression in PASMCs. Incubation of PASMCs with BAPTA/AM, a cell‐permeable intracellular calcium chelator, did not affect the increases in calpain activity induced by PDGF‐BB, 5‐HT, ET‐1, IL‐6, and H2O2.ConclusionPDGF‐BB, 5‐HT, ET‐1, IL‐6, and H2O2 induce the activation of calpain. The mechanism is not due to increase in intracellular calcium. Supported by NIH and FAMRI
Loss of PPARγ promotes NF‐κB activation, Nox4 induction, and proliferation of human pulmonary artery smooth muscle cells
Authors: Bijli Kaiser M , Kang Bum‐Yong , Murphy Tamara , Hart C Michael 
Published: June 2021

Hypoxia stimulates pulmonary hypertension (PH) in part by increasing the proliferation of pulmonary vascular wall cells. Recent evidence suggests that signaling events involved in hypoxia‐induced cell proliferation include sustained Nuclear Factor‐kappaB (NF‐κB) activation, increased NADPH oxidase4 (Nox4) expression, and downregulation of peroxisome proliferator‐activated receptor gamma (PPARγ) levels. To further understand the role of reduced PPARγ levels in PH pathobiology, siRNA was employed to reduce PPARγ levels in human pulmonary artery smooth muscle cells (HPASMC) in vitro. PPARγ siRNA reduced PPARγ levels to an extent comparable to those observed under hypoxic conditions. PPARγ depletion activated NF‐κB as determined by phosphorylation of RelA/p65 (NF‐κB) at Ser536 and degradation of its inhibitory protein, I‐kappaB alpha. PPARγ depletion also induced the expression of the NF‐κB target gene, Nox4 and increased HPASMC proliferation as determined by MTT assay and elevated levels of proliferating cell nuclear antigen. Furthermore, treatment with PEG‐catalase attenuated HPASMC proliferation caused by PPARγ depletion. Taken together, these findings provide novel evidence that reductions in PPARγ levels are sufficient to promote HPASMC proliferation via NF‐κB activation, Nox4 induction, and H2O2 generation.Supported by: Atlanta VA Research Service, NIH DK074518 and HL102167, and AHA‐SDG
Effects of acetylcholine and cholinergic antagonists on the activity of nucleus of the solitary tract (NTS) neurons
Authors: Furuya Werner Issao , Colombari Eduardo , Ferguson Alastair Victor , de Almeida Colombari Debora Simoes 
Published: June 2021

It has been shown that acetylcholine (ACh) can depolarize neurons in the NTS (Shihara et al., 1999). Thus, in the present study, we tested the electrophysiological effects of ACh, alone or combined with cholinergic antagonists, on the commissural NTS (cNTS) or intermediate NTS (iNTS). Coronal slices of the brainstem containing either cNTS or iNTS subnuclei, 600 μm apart, were obtained from male Sprague‐Dawley rats (p21–28 days) and used in whole cell patch clamp – current clamp recordings. ACh (10 mM, 1 min) was applied to slices 10 min before and 5 min after application of atropine (ATR, non‐selective muscarinic antagonist, 10 μM, 5 min) or mecamylamine (MEC, non‐selective nicotinic antagonists, 10 μM, 5 min). In cNTS, 7/12 neurons (58%) were depolarized by ACh (6.9 ± 1.5 mV), effects which were maintained in the presence of ATR (Control 5.1 ± 1.4, ATR 4.8 ± 0.7 mV, p>;0.05, n=6). However, MEC inhibited the ACh actions on cNTS (Control 10.4 ± 2.7, MEC 1.3 ± 0.9 mV, p<0.05, n=5). ACh also depolarized (9.8 ± 2.4 mV) 13/17 neurons (76%) of the iNTS. ATR reduced the depolarization induced by ACh (Control 12.5 ± 2.8, ATR 7.8 ± 2.4 mV, p<0.05, n=8), as well as MEC (Control 9.5 ± 2.0, MEC 2.9 ± 1.0 mV, p<0.05, n=8). These data demonstrate that ACh depolarizes cNTS neurons through actions on nicotinic receptors, while depolarizing effects in iNTS are apparently mediated by both receptors.Supported by: FAPESP, Canadian Inst. for Health Research
The role of β1 adrenergic receptor in Non‐Alcoholic Fat Liver Disease development
Authors: Fernandes Gustavo Werpel , Marcelino Cícera Pimenta , Brum Patricia Chakur , Passarelli Marisa , da Costa Bocco Bárbara Miranda Leite , Ribeiro Miriam Oliveira 
Published: June 2021

Non‐Alcoholic Fat Liver Disease (NAFLD) is characterized by the development of macrovesicular steatosis in the absence of significant consumption of alcohol, which can progress to nonalcoholic steato‐hepatitis (NASH). Knockout mice for the β1 adrenergic receptor (β1KO) are obese when placed on high fat diet (HFD) and develop NASH with severe steatosis and fibrosis. The aim of this study was to determine if β1 adrenergic receptors have a direct role in NASH development or if this abnormality is due to the severe obesity observed in these mice. For that we analyzed genes related to lipid metabolism in the liver of obese β1KO. Fatty acids, triglycerides and cholesterol synthesis were increased in β1KO HFD (ChREBP: 5.55±0.2 vs. 2.28±0.04 WT, p<0.05; SREBP1c: 2.52±0.4 vs. 1.32±0.02 WT, p<0.05; DGAT2: 2±0.3 vs. 1.3±0.1 WT, p<0.05; SREBP2: 3.22±0.5 vs. 0.67±0.06 WT, p<0.05) resulting in hepatic triglycerides accumulation whereas hepatic secretion of lipoproteins were decreased (MTTP: 0.32±0.01 vs. 0.6±0.03 WT, p<0.05). These data showed an imbalance in lipoproteins synthesis and export, resulting in NASH. In conclusion, β1 adrenergic receptor has a direct influence on expression of genes related to lipid metabolism, and its absence leads to NASH when mice are treated with HFD.Supported: FAPESP/CAPES
Intranasal administration of IL‐37 attenuates bleomycin induced experimental lung injury/fibrosis
Authors: Park sung woo , Kim Cho Rong , Lee Eun Hee , Kim Jung Hyun , Park Jong Sook , Lee June Hyuk , Jang An Soo , Kim Do Jin , Uh Soo‐taek , Kim Yong Hoon , Park Choon‐sik 
Published: June 2021

Lung fibrosis can occur as a result of various inflammatory and oxidative conditions. Idiopathic pulmonary fibrosis(IPF) is the most common entity with a poor prognosis resulting high mortality rate. Currently, there are no proven effective treatment for inhibitor of innate inflammation and immunity. To evaluate intranasal treatment of IL‐37 have therapeutic effect on bleomycin‐induced lung injury/fibrosis in mice.Histological examinations, collagen assay, ROS assay and cytokine measurements including IL‐1b, TNF‐a and TGF‐b1 were performed in bleomycin‐treated mouse lung tissues with or without the administration of IL‐37. Lung IL‐37 expression from the patient with IPF and controls were measured by immunohistochemistry and immunoblot. H2O2 induced apoptosis that were measured by Annexin V/PI stain in A549 cells with or without presence of IL‐37.Compared with control mice, IL‐37 treated mice had significantly less lung inflammation, collagen deposition, oxidative damage as well as decreased levels of BAL fluid IL‐1b, TNF‐a and TGF‐b1. Treatment of IL‐37 significantly inhibit cell apoptosis dose dependent manner. Lung IL‐37 protein expression was significantly decreased in patients with IPF than controls.Local treatment with IL‐37 is effective against the development of experimental lung injury/fibrosis. Anti‐apoptotic and anti‐oxidative activity of IL‐37 contribute at least partly its anti‐fibrotic effect on the experimental fibrosis.
Altered skeletal muscle respiration in patients with COPD: mitochondrial density or dysfunction?
Authors: Gifford Jayson Reed , Garten Ryan S , Trinity Joel , Park Songyoung , Layec Gwenael , Larsen Steen , Richardson Russell S 
Published: June 2021

INTRODUCTIONWe sought to determine if the blunted mitochondrial respiration typically observed in the skeletal muscle of patients with chronic obstructive pulmonary disease (COPD) is solely related to changes in mitochondrial density or if qualitative changes in respiration occur.METHODSCombinations of substrates (malate, glutamate, succinate, and ADP) and inhibitors (oligomycin) were used to measure complex I (CI) and complex II (CII) driven state 3 respiration separately and in combination in permeabilized muscle fibers from the vastus lateralis of 9 healthy controls (67±2 years) and 11 COPD patients (FEV1= 56±6%; 63±3 years). State 4 respiration and citrate synthase (CS) activity were measured using these same fibers.RESULTSCompared to controls COPD patients had blunted CI driven state 3 respiration (37.2±4.1, 23.7±2.7 nM/min/mg, respectively) and blunted state 3 respiration with CI and CII (47.2±5.1, 33.7±3.8 nM/min/mg, respectively) (P<0.05) while state 3 driven by CII alone was similar between groups. CS activity and state 4 respiration were not different between groups.CONCLUSIONSGiven that CS activity, an indicator of density, was similar between groups, the blunted respiratory capacity in these COPD patients appears to be related to an attenuation of CI driven respiration. These data indicate that COPD results in qualitative changes in mitochondrial respiration of skeletal muscle.
Natural killer cell maturation is blocked by mTOR inhibition in C57Bl/6 mice
Authors: Clinthorne Jonathan F , Gardner Elizabeth M 
Published: June 2021

Recent work established a pathway by which the energy sensitive kinase mammalian target of rapamycin (mTOR) regulates T cell biology, and this pathway is directly influenced by energy intake. Energy restriction (ER) is a dietary intervention shown to increase lifespan and reduce the incidence of tumors in rodents. The objective of this study was to examine the role of mTOR in NK cell metabolism and biology, based on the observation that ER results in fewer mature NK cells. NK cells from 40% ER mice exhibited mTOR inhibition directly ex vivo, and reduced expression of the transcription factors Eomes and T‐bet, which are required for NK cell maturation. Consequences of mTOR inhibition on NK cell biology was examined in vitro and revealed IL‐12 + IL‐18 induced NK cell maturation and function was impaired following rapamycin treatment. mTOR inhibition reduced upregulation of metabolic transporters, and repressed expression of NK cell maturation markers. Concurrently, mTOR inhibition in NK cells blocked upregulation of transcription factors Eomes and T‐bet following stimulation. Mature NK cells play a critical role in killing tumor cells and here we show NK cell maturation is linked to metabolic signaling through mTOR. Thus, manipulation of energy intake or energy sensitive pathways directly influences NK cell maturation, which has significant implications during the immune response to cancers or viral infections.Grant Funding Source: R01AG034949
Sound advice or biased reporting? Breakfast as a strategy to reduce or prevent obesity or weight gain
Authors: Brown Andrew W , Brown Michelle M Bohan , Allison David B 
Published: June 2021

Eating breakfast to control weight is a strategy presumed true without sufficient supporting evidence. We investigated whether biased reporting in primary literature exaggerates the protective effect of breakfast against obesity. From 92 identified studies of breakfast and obesity (all observational), ORs were calculated and meta‐analyzed from 88 study groups in 57 publications representing 30 countries. The resulting p‐value of p<10−42 demonstrates gratuitous repetition of the breakfast‐obesity presumption. No publication bias was detected. Analysis of 88 of the 92 studies’ abstracts revealed that authors biased the reporting of their own findings: breakfast‐obesity associations were more likely to be mentioned in abstracts’ conclusions if results were pro‐breakfast, compared to associations that showed mixed, negative, or no relationships (65% vs. 39%, p=0.0492); and causal language was used in 26% of abstracts that mentioned breakfast and weight in the conclusions. Citing of others’ work was also biased: 67% of relevant citations of one breakfast RCT were overly positive toward breakfast (2% overly negative), while 48% of relevant citations of a case‐series paper inappropriately used associative or causal language. In conclusion, there is evidence of biases in the breakfast literature that misleadingly exaggerate the strength of the evidence for a presumed protective effect against obesity.Grant Funding Source: NIDDK P30DK056336 and NIDDK T32DK62710–01A1