bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial DNA damage associated activation of NLRP3 inflammasome impairs host defense during P. aeruginosa infection
Authors: Bedi Brahmchetna , Maurice Nicholas M , Yuan Zhihong , Prasla Zohra , Sadikot Ruxana T 
Published: June 2021

P. aeruginosa is an opportunistic pathogen and a significant contributor of recalcitrant multidrug resistant infections. Immunocompromised and hospitalized patients are especially susceptible to rapid incessant infections. Therapies modulating innate immune defenses of the host are urgently needed for managing resistant infections. We have previously shown that the respiratory epithelium is an important contributor to host defense against P. aeruginosa and it's (quorum sensing) QS molecule N‐3‐oxo‐dodecanoyl‐L‐Homoserine lactone (C12‐HSL). Infection with PAO1 as well as C12‐HSL treatment induces mitochondrial DNA (mtDNA) damage. Emerging studies have shown that mtDNA acts as potential danger associated molecular patterns (DAMPs), which can in turn act as a driver of downstream inflammatory responses. We hypothesize that P. aeruginosa infection causes increase in mitochondrial membrane potential transition and ROS generation, causing release of damaged mtDNA in the cytosol as a DAMP. Presence of DAMPs in the cellular milieu activates TLR9 and the assembly and activation of the inflammasome mediated innate immune responses such as the secretion of IL‐1b and IL‐18. Exacerbation of inflammatory responses, attenuates host defense and enhances infection susceptibility. Normal bronchial epithelial (BEAS‐2B) cells infected with multiple P. aeruginosa strains, namely PAO1, PA1O3 and PAK showed a significant increase in the mRNA and protein expression of NLRP3, AIM2, nod like receptors (NLRs) and the other components of the inflammasome complex. This increase in expression was concomitant with the increase mtDNA damage. An increase in Toll like receptor 9 expression was also noted in the P. aeruginosa infected BEAS‐2B cells. The functional impact downstream of these interactions is the reduction in expression of epithelial immune mediators such as anti‐microbial peptides (AMPs) including human beta defensin (hBd2) and cathelicidin (LL37) as well as loss of epithelial barrier integrity. Studies exploring the inhibition of NLRP3 inflammasome using compounds such as Glibenclamide are currently underway and can be exploited as a therapeutic target to enhance host defensesSupport or Funding InformationDepartment of Veterans Affairs 2I01BX001786 (RTS)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Long Term Hypoxia Reduces Antioxidant Levels and Causes a Glycolytic Shift in Neonatal Sheep Pulmonary arteries
Authors: Kafeero Isaac , Alvarez Rafael , Lopez Vanessa , Bosviel Remy , La Frano Michael , Newman John , Fiehn Oliver , Zhang Lubo , Wilson Sean M 
Published: June 2021

Gestational Hypoxia is a common prenatal stress caused by high altitude living, smoking, and other prenatal disorders. Such hypoxic insult can cause abnormalities in lung development that result in pulmonary hypertension in the newborn. Hypoxia is known to cause oxidative stress and accentuate glycolysis in adult tissues, effects which are intertwined with the development of various diseases. However, the adaptive responses of metabolism to long term hypoxia (LTH) in the fetal pulmonary vasculature is not nearly as well understood. The current work tests the hypothesis that following gestational LTH there is reduced antioxidant capacity and increased cellular glycolysis in neonatal sheep. For this study, normoxic pregnant and non‐pregnant sheep were obtained from Nebeker Ranch in Lancaster, CA (~700 meters) and were either sent to Loma Linda for study or to the White Mountain Research Station at an altitude of 3800 meters to induce LTH. After 110+ days at high altitude, animals were transported to Loma Linda University for the study. Pulmonary arteries of adult, 2‐week‐old newborn, and near‐term fetal sheep were isolated and frozen for analysis of primary metabolites. Metabolite levels were analyzed using Gas Chromatograph Time of Flight mass spectrometry (GC‐TOF MS) and visualized using enrichment and pathway analyses. LTH decreased the concentration of the antioxidant glutathione (GSH) and increased lactic acid, a byproduct of glycolysis, in adult and fetus. In the newborn LTH also decreased citric acid, a key intermediate in the Krebs cycle. These data indicate that the mother does not protect the pulmonary vasculature of the fetus from long term hypoxic stress due to gestation at high altitude. Thus, the fetus appears to be vulnerable even at modest altitudes to metabolic shifts and oxidative stress. Effects of these metabolic changes may persist after birth and contribute to the development of disease in the neonate or later in life.Support or Funding InformationThis material is based upon work supported by NIH grants P01HD083132 (LZ) and 1U24DK097154 through a pilot project grant to SMW as well as P20MD006988. IK was an Undergraduate Summer Research Fellow while RA was an Apprenticeship Bridge to College Scholar through the Center for Health Disparities and Molecular Mechanisms at Loma Linda University. VL is a recipient of the American Physiological Society's Short‐Term Research Education Program to Increase Diversity in Health‐Related Research (STRIDE) Fellowship funded by the APS and a grant from the National Heart, Lung and Blood Institute R25HL115473.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Oxidative deregulation of ferrochelatase mediates transferrin receptor‐induced remodeling in pulmonary arterial smooth muscle cells in monocrotaline‐induced pulmonary arterial hypertension
Authors: Alhawaj Raed , Ghadhanfar Elham , Cherian Susan 
Published: June 2021

Pulmonary arterial hypertension (PAH) is driven by pulmonary arterial smooth muscle cell (PASMC) vasoconstriction and remodeling. One of the many drivers of PAH‐PASMCs remodeling is increased transferrin receptor‐1 (TFR‐1) expression. Under pro‐PAH conditions, PASMCs exhibit elevated reactive oxygen species (ROS) production which may disrupt ferrochelatase normal heme production. We evaluated the role played by ROS‐deregulated ferrochelatase in TFR‐1‐mediated PAH‐PASMCs remodeling. Intra‐lobar pulmonary arteries (PA) isolated from monocrotaline‐induced PAH model in Sprague‐Dawley rats have shown an up‐regulation of ferrochelatase expression, that can be a result of hypoxia‐inducible factor (HIF) mediated up‐regulation to compensate for decreased ferrochelatase catalytic activity. Decreased ferrochelatase activity was evident in the decreased levels of hemin (oxidized form of heme) in isolated PAH‐PAs. Endothelin‐1 (ET‐1), which is an inducer of mitochondrial ROS and is one of the mediators of PAH; was used in a 24‐hour organ culture of isolated endothelium‐removed bovine pulmonary arteries (BPA). ET‐1 cultured BPAs have shown decreased hemin levels and increased TFR‐1 expression. Thus, ROS‐deregulated ferrochelatase may promote vascular remodeling in PAH through the impairment of hemin‐mediated downregulation of TFR‐1 receptors in PASMCs.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Intermittent Hypoxia Disrupts Synaptic Long Term Depression
Authors: Arias Alejandra , Nwakudu Chinwendu , Khuu Maggie A , Garcia Alfredo J 
Published: June 2021

Long term potentiation (LTP), activity‐dependent synaptic strengthening, and long term depression (LTD), activity dependent synaptic attenuation, are two forms of synaptic plasticity whose underlying mechanisms permit flexibility in synaptic communication and serve as substrates for learning and memory. Intermittent hypoxia (IH), a hallmark of sleep apnea, is known to impair spatial learning and memory. The objective of this study is determine how LTP and LTD are affected by IH. We hypothesize that IH impedes efficacy of activity dependent synaptic plasticity in the hippocampus, a brain structure important to learning and memory. We examined in vitro LTP and LTD in hippocampal brain slices following IH exposure. Electrophysiological recordings showed that LTP in area CA1 could be evoked in control and IH exposed groups, yet the magnitude of LTP following IH was decreased (LTP: control 184.72±15.93% vs. IH 145.35±6.34% baseline) . While LTD could be elicited in the control group (63.31±3.03% baseline), LTD could not be evoked from the IH exposed group (104.18±3.44% baseline). Although IH impacted both forms of long term synaptic plasticity, this was not accompanied by differences in paired‐pulse facilitation, indicating that short‐term plasticity was unaffected by IH. These findings demonstrate that IH affects mechanisms of activity‐dependent regulation of synaptic efficacy, which may involve IH‐dependent changes in NMDA receptor contribution to these phenomena. Our findings further contribute to understanding potential neurophysiological changes that may decrease the threshold for cognitive decline associated with sleep apnea.Support or Funding InformationThis work was supported by NIH R01 NS10742101 (AJG).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Unrestrained Barometric Plethysmography During Air and Hypoxic Exposures in Old Mice Fed a Capsaicin Rich or Control Diet
Authors: Russell Jacob D , Receno Candace N , Cunningham Caitlin M , Deruisseau Keith C , Deruisseau Lara R 
Published: June 2021

Capsaicin is the primary active ingredient in chili peppers and is an agonist for transient receptor potential vanilloid 1 (TRPV1). TRPV1 receptors are found in mammalian respiratory airways and pleural afferents (Takemura, 2008). The stimulation of these receptors by capsaicin augments respiratory responses in anesthetized mice with low doses (Roy, 2012) and increases breathing frequency of anesthetized mice upon intracarotid injection (Wang, 2006). Because pulmonary functions tend to deteriorate with age, our study aimed to examine the effects of dietary capsaicin on the respiratory response of aged mice. We hypothesized old mice fed capsaicin would display maintained ventilation compared to mice fed a control diet. Unrestrained barometric plethysmography (UBP) was used to quantify breathing frequency (F, breaths/min), tidal volume (VT, mL/breath), minute ventilation (VE, mL/min), ratio of VT to inspiration time (VT/IT, mL/sec), and the ratio of VE to expired carbon dioxide (VE/VCO2) in mice breathing air (20.93% O2 and .05% CO2) and exposed to hypoxic conditions (10 % O2, 0 % oxygen) for 15 minutes. C57BL/6J male mice were tested at 22 months of age prior to any dietary intervention and again at 23 months of age after one month of a lecithin control diet (CON; 50mg/kg per food weight; n=12) or a capsaicin rich diet (CAP; 50mg/kg per food weight; n=10). Data are presented as % change from pre‐values at 22 months of age; mean±SD. There were no differences between groups (p>0.05) with air exposure for F (CON: −3.7 ± 26.9% vs CAP: 19.5 ± 51.7% breaths/min), VT ( CON: 13.8 ± 40.9% vs. CAP: −3.7% ± 22.4% mL/breath), VE (CON: 3.1 ± 35.6% vs. CAP: 16.0 ± 53.2% mL/min), VT/IT (CON: 55.6 ± 89.6%vs. CAP: 37.8 ± 109.1% mL/sec), or VE/VCO2 (CON: −13.7 ± 45.4% vs. CAP: 11.0 ± 72.1%). Hypoxic exposure revealed no differences (p>0.05) between groups for F (CON: −1.0 ± 23.0% vs. CAP: 6.3 ± 24.9% BPM), VT (CON: 29.0 ± 60.5% vs. CAP: 28.1 ± 49.8% mL/breath), VE (CON: 13.4 ± 33.2% vs. CAP: 17.8 ± 36.6% mL/min), VT/IT (CON: 11.4 ± 29.6% vs. CAP: 12.7 ± 48.3% mL/sec), or VE/VCO2 (CON: −15.1 ± 38.6% vs. CAP: 10.5 ± 65.6%). Therefore, our hypothesis was not supported as there were no differences between CON and CAP respiratory responses. We conclude that 50mg/kg of capsaicin in the diet does not alter ventilation in old mice.Support or Funding InformationJDR supported by the McDevitt Undergraduate Research Fellowship in Natural Science and CNR supported by 1 R15 HD076379‐01A1S1This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Involvement of the opioid system in the 17β‐estradiol‐induced enhancement of sucrose intake in ovariectomized rats
Authors: Iida Kurumi , Kanamori Konomi , Kondo Sayaka , Izumi Ayana , Morimoto Keiko , Takamata Akira 
Published: June 2021

We previously found that 17β‐estradiol (E2) replacement in ovariectomized rats enhanced progressive increase in 10% sucrose solution intake. In the present study, we hypothesized that the E2‐induced enhancement of sucrose intake is mediated by the opioid system, which is known to play an important role in excessive intake of highly palatable foods. Female Wistar rats were ovariectomized and those rats were assigned to the E2‐treated group (E2 group) or cholesterol‐treated group (Veh group). In the experiment 1, we examined the effect of naltrexone (NTX), an opioid receptor antagonist, on intake of sucrose solution. In this experiment, rats were continuously infused with NTX or saline by an osmotic minipump, and intake of 10% sucrose solution was measured for 14 days. The NTX treatment reversed E2‐induced enhancement of sucrose solution intake. In the experiment 2, we investigated whether the μ‐opioid receptors in the nucleus accumbens (NAc) is involved in the effect of E2‐induced enhancement of sucrose intake. We performed microinjections of a μ‐opioid receptor agonist D‐Ala2, NMe‐Phe4, Glyol5‐enkephalin (DAMGO), NTX or saline into the nucleus accumbens (NAc) in each rat. After microinjections, rats were tested the two‐bottle choice paradigm with 10% sucrose solution and water. Injection of NTX in the NAc reduced sucrose intake in the both groups, and the intake was not different between the groups. These results suggest that the E2‐induced enhancement of sucrose intake is possibly mediated by the opioid system. Also, the opioid receptors in the NAc is a potential site of the action of the E2‐induced enhancement of sucrose intake.Support or Funding InformationJPSP KAKENHI #15K12355 and 24500975 to Akira TakamataThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Obesity by High Fat Diet Decreases the Abundance of MC4R Protein in the Paraventricular Nucleus of the Hypothalamus without Reducing the Number of MC4R Neurons
Authors: Nyamugenda Eugene , Russell Susan , Cooney Kimberly , Griffin Haven , Hoang Vincent Ngoc , Phelan Kevin D. , Baldini Giulia 
Published: June 2021

The hypothalamus plays a central role in maintaining normal energy homeostasis. The arcuate nucleus (ARC) of the hypothalamus receives anorexigenic signals from the periphery mediated by increased circulating leptin and insulin, which bind to receptors expressed by proopiomelanocortin (POMC) neurons in the ARC. When activated, POMC neurons projecting to the paraventricular nucleus (PVN) of the hypothalamus release α‐Melanocyte‐stimulating hormone (α‐MSH) at this location. In the PVN, α‐MSH binding to the melanocortin 4 receptor (MC4R) signals to decrease food intake and increase energy expenditure. Exposure to HF diet induces, in male, but not female mice, injury to POMC neurons with neuronal loss and loss of α‐MSH abundance. It remains unclear whether other types of hypothalamic neurons are also being affected by exposure to HF diet. In this respect, we have found that exposure to HF diet induces loss of Single‐Minded Family BHLH Transcription Factor 1 (Sim1) neurons in the PVN of male and female mice. Sim1 neurons in the PVN include the population of MC4R neurons. Here we asked whether in the PVN of mice exposed to HF diet there is a loss of MC4R neurons and/or decreased abundance of MC4R protein. When exposed to HF diet, male and female Sapphire mice expressing GFP under the MC4R have increased body weight as compared to the control mice fed low fat (LF) diet (by 39.03 ± 5.37% and 24.19 ±4.18%, respectively). Both male and female Sapphire mice exposed to HF diet have the same number of MC4R neurons as compare to controls exposed to LF diet. These data indicate that MC4R neurons are resistant to HF diet. To test whether exposure to HF diet reduces the abundance of MC4R protein, we generated knock‐in mice with human influenza hemagglutinin (HA) epitope tag at the C‐terminus of endogenous MC4R (MC4R‐HA mice). As compared to control, male and female MC4R‐HA mice exposed to HF diet had increased body weight (by 53.84 ± 7.00% and 45.57 ± 6.23% respectively), increased caloric intake by (39.28 ± 16% and 37.52 ± 10.85%, respectively) and reduced MC4R protein abundance in the PVN (by 63.27 ± 18.54 % and 67.77 ± 18.00 %). The data indicate that loss of MC4R protein, rather than of MC4R neurons, is a feature of male and female mice exposed to HF diet, thereby suggesting expression of MC4R as a target for anti‐obesity therapy.Support or Funding InformationThis work was supported by National Institutes of Health Grants R01‐DK102206 (to G.B.), by UL1TR000039, and by Intramural Funding Support from the University of Arkansas for Medical Sciences College of Medicine Research Council.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mechanism of action of catestatin as an autocrine modulator regulating catecholamine secretion from chromaffin cells at the of splanchnicoadrenomedullary synapse
Authors: Mahata Sushil Kumar , Sahu Bhavani Shankar , Mahata Sumana , Bandyopadhyay Keya , Mahata Manjula , Webster Nicholas J.G. , Eiden Lee E 
Published: June 2021

ObjectiveThe chromogranin A (CgA)‐derived peptide catestatin (CST: human CgA352–372) is thought to act as an autocrine modulator of catecholamine secretion from the adrenal medulla in vivo. Here, we examined how CST affects nicotine‐ and PACAP‐induced secretion from, and protein resynthesis within, dense core (DC) vesicle (DCV) quanta containing catecholamines and chromogranin/secretogranin proteins in PC12 cells.Methods and ResultsDepletion of norepinephrine (NE) from PC12 cells treated acutely (0.5 hours) with either nicotine (60 μM)‐ or PACAP (0.1 μM) was reversed by CST (2 μM), as was 3H‐NE release elicited by both secretagogues. DCV and DC area and diameter, evaluated by Transmission Electron Microscopy, were both decreased after treatment with either nicotine or PACAP, and this morphological effect was likewise reversed by CST. Nicotine or CST alone increased expression of CgA protein (but not CgB), and, in combination, elicited an additional increase in CgA protein, implying that nicotine and CST utilize separate signaling pathways to activate expression of CgA. In contrast, PACAP increased expression of CgB protein (but not CgA), indicating differential regulation of CgA and CgB proteins by cholinergic and peptidergic stimulation. Although CST augmented expression of tyrosine hydroxylase (TH) protein, it did not induce synthesis of catecholamines, presumably due to its inability to cause post‐translation activation of TH via serine phosphorylation. Increased area and diameter of DCVs, and their DCs after CST, CST+nicotine and CST+PACAP are consistent with increased quantal size. Decreased quantal size is possibly mediated by increased synthesis of granulogenic proteins: CgA after CST treatment; CgA after CST+nicotine treatment; and CgB after CST+PACAP treatment.ConclusionBased on our results obtained in PC12 cells, we suggest that the CgA‐derived peptide CST acts as a paracrine factor during ACh or PACAP stimulation of secretion from chromaffin cells of the adrenal medulla, modulating both the extent of secretory stimulation by splanchnic nerve firing, and the repletion of secretory granule content after bouts of secretory activity.Support or Funding InformationSupported by grants from the VA (I01BX000323 to S.K.M.; I01BX002709 to N.J.G.W), and the NIH (MH002386 to L.E.E.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Progesterone Induces Neuroprotection in a Model of Neonatal Hypoxic‐Ischemic Brain Injury
Authors: Tassinari Isadora D’Ávila , Fabres Rafael Bandeira , de Menezes Camboim Yahi , de Araujo Elcyus Boff Marques , Nunes Ricardo Ribeiro , Andrade Mirella Kielek Galvan , Rodrigues Thais Lopes , Netto Carlos Alexandre , Ribeiro Maria Flavia Marques , de Fraga Luciano Stürmer 
Published: June 2021

Neonatal hypoxic‐ischemic encephalopathy (HI) is a major cause of neurologic deficits in newborns. Since administration of progesterone (PROG) has shown neuroprotective effects in adult models of nervous system injury, we evaluated the effects of PROG in a model of neonatal HI.Seven‐days‐old rats (n=6) were subjected to a surgery for ligation of the common right carotid artery followed by exposure to an hypoxic atmosphere (8% of oxygen) for 60 min. PROG (10 mg/kg) was administered before and/or after HI. Rats were euthanized one week after HI and their brains were processed for histology or Western blot analysis. Hemispheric and hippocampal volumes were measured and apoptotic cells were counted in the CA1 and CA3 areas of the hippocampus. Proteins involved in cell death and survival (caspase‐3 and Akt) were also analyzed. This study was approved by the local Institutional Animal Care and Use Committee (UFRGS #26669; HCPA #140578).The hemispheric and hippocampal lesion caused by HI was reduced by PROG treatment. The number of apoptotic cells in CA1 and CA3 areas was also decreased by PROG administration. Expression of p‐Akt was unaffected by HI but was significantly increased in the hippocampus of PROG‐treated animals. Moreover, administration of PROG reduced hippocampal cleaved caspase‐3 expression.In summary, PROG administration reduced brain damage and neuronal apoptosis in neonatal animals submitted to HI. This neuroprotective effect is probably related to the capability of PROG in regulating caspase‐3 and Akt signaling pathways.Support or Funding InformationThis study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq‐Brazil), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES‐Brazil), Pró‐Reitoria de Pesquisa (PROPESQ/UFRGS‐Brazil), and Fundo de Incentivo à Pesquisa e Eventos do Hospital de Clínicas de Porto Alegre (FIPE/HCPA‐Brazil).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.