bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intermittent Normobaric Hypoxic Training Protects the Brain by Regulating Microglia Phenotype
Authors: Joshi Akita , Han Heping , Lewis Sally , Ryou Myoung‐gwi 
Published: June 2021

IntroductionEthanol Withdrawal (EW) syndrome is an etiologically important factor linked to the ischemia and reperfusion injuries, including ischemic stroke. In the US, ischemic stroke is the 4th leading cause of death and the first cause of adult disability. Previously we showed that intermittent normobaric hypoxic training (IHT) protects the brain from EW syndrome by reducing ROS and increasing protective proteins. Pro‐inflammatory microglia has been studied in various CNS diseases. However, the function of microglia in the IHT‐induced brain protective mechanism is not yet thoroughly explored. In here, we focused on how IHT influence on regulating the phenotype of microglia, a pivotal resident phagocytic cell in the brain, in the in vitro IHT model.MethodsMouse microglia cells, EOC20 cell, underwent three days of IHT program which composed of 5–7 cycles of hypoxia/normoxia. O2 concentration was gradually decreased from 2.5% to 2 % each daily training cycle. Two sessions of EW treatment was done as following; EtOH (100 mM) for 16 hrs followed by 6 hrs of EtOH cessation. Cells were assigned into four groups; 1) non‐treated control, 2) IHT, 3) EW, 4) IHT+EW. Cell viability was evaluated by Calcein AM assay. Immunocytochemistry and flow cytometry were applied to determine the phenotype of microglia; CD 68 (M1), CD 206 (M2). The expression of mRNA of pro‐ and anti‐inflammatory cytokines were examined with quantitative real‐time rt‐PCR. Additionally, protein contents, which play a role in cerebral protection, were quantified by immunoblot assays. Data were expressed as mean ± SEM. Two factor ANOVA analysis and Tukey's multiple comparison test was used. P value < 0.05 was considered as a significant value.ResultsEW reduced cell viability and IHT was able to salvage the microglia from EW stress. IHT‐induced protection was mediated by increased HIF‐1α and activated Erk, an anti‐apoptotic protein kinase. The expression of CD 68 was not reduced with IHT vs. EW, but CD 206 was significantly increased in the IHT group vs. non‐IHT groups. An increased pro‐inflammatory phenotype of microglia was observed in the flow cytometry. IHT significantly decreased the expression of TNF‐α and IL‐6, pro‐inflammatory cytokines.ConclusionIHC drives the microglia toward anti‐inflammatory phenotype, which could be an important factor in the IHC‐induced cerebral protective mechanism.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Placental Ischemia‐Induced Hypertension Is Abolished by Adrenergic Receptor Blockade
Authors: Spradley Frank T. 
Published: June 2021

Hypertensive disorders of pregnancy are the number one cause of pregnancy‐related deaths in the United States. Preeclampsia is a disorder of maternal hypertension and vascular dysfunction presenting in the second half of pregnancy along with fetal growth restriction. Currently, there are no steadfast therapies besides early delivery of the fetus and ischemic placenta, which releases pro‐hypertensive factors into the maternal circulation. The sympathetic nervous system might be a novel target in treating preeclampsia, as sympathetic nervous activity is found to be increased in preeclamptic vs. normal pregnant women. However, it is unknown if the sympathetic nervous system mediates the development of placental ischemia‐induced hypertension. In this study, the hypothesis was tested that adrenergic receptor blockade prevents placental ischemia‐induced hypertension. Wistar Hannover rats were randomized to receive reduced uterine perfusion pressure (RUPP, N=15) or Sham RUPP (N=20) surgeries on gestational day 14 and examined at day 19. In RUPP vs. Sham rats, respectively, mean arterial blood pressure (MAP) was increased (121 ± 3 vs. 102 ± 1 mmHg, P<0.05) without a change in heart rate (421 ± 7 vs. 423 ± 4 bpm). Average fetal weights (1.87 ± 0.04 vs. 2.11 ± 0.03 g) and placental weights (0.50 ± 0.02 vs. 0.57 ± 0.01 g) were lower (P<0.05) in RUPP dams. In RUPP over Sham rats, vasoconstriction induced by the alpha‐adrenergic receptor agonist, phenylephrine, was greater in isolated renal interlobar arteries (Emax: 322 ± 19 vs. 251 ± 12 % of KCl response). The Emax response to KCl was not different between RUPP or Sham rats, in sequence: 100 ± 24 vs. 87 ± 14 % increase in force. A subset of RUPP (N=9) and Sham (N=9) rats received combined terazosin and propranolol (3 mg/kg per day of each, subcutaneous osmotic minipump) to block alpha‐ and beta‐adrenergic receptors, respectively, beginning the day of surgery on gestational day 14. By day 19, adrenergic blockade abolished the development of hypertension in RUPP rats (105 ± 2 mmHg, P<0.05) and reduced their heart rate (343 ± 21 bpm, P<0.05) with a lesser reduction detected in treated Sham rats for MAP (97 ± 2 mmHg, P<0.05) and heart rate (387 ± 9 bpm, P<0.05). Treatment did not alter average fetal weights (1.89 ± 0.05 and 2.11 ± 0.03 g) or placental weights (0.47 ± 0.02 and 0.50 ± 0.03 g) in RUPP and Sham rats, in turn, compared to their untreated counterparts. In conclusion, placental ischemia‐induced hypertension depends on activation of the sympathetic nervous system. The mechanisms responsible for this enhanced sympathetic nerve activity and adrenergic receptor signaling remain unknown but are likely to involve factors released from the ischemic placenta.Support or Funding Information4R00HL130577‐02This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effects of Subconcussive Impacts on Heart Rate Variability In Female Youth Soccer Players
Authors: Bonn Marquise , Harriss Alexandra , Dickey James P. 
Published: June 2021

BackgroundANS function can be measured noninvasively and relatively inexpensively through heart rate variability (HRV). Reduced HRV is representative of an uncoupling between the ANS and cardiovascular system, which may be proportional to the severity of a neurological injury. Reduced HRV has been observed in patients diagnosed with a sport‐related concussion, and therefore may be a useful outcome measure in identifying the chronic effects of heading during a youth soccer season.ObjectivesThe purpose of this study was to evaluate the effects of one season of competitive soccer, with the inherent subconcussive header impacts, on autonomic function in female youth soccer players.ParticipantsTwenty‐three female youth soccer players (13.4 ± 0.84 years old) were recruited from three competitive soccer teams.MethodsThe number of headers performed during the season were quantified using game video analysis. Players that performed fewer than the average number of headers (20) at the end of the season were classified into the “low header” group (N=13), while players with 20 or more headers at the end of the season were classified into the “high header” group (N=10). A five‐minute resting electrocardiogram data was collected from all players at baseline and post‐season. These data were analyzed using a two‐way mixed ANOVA in order to calculate heart rate variability time‐domain and frequency‐domain measures, which included mean heart rate, standard deviation of the N‐N interval, total power, low frequency, high frequency, and low to high frequency ratio (LF/HF).ResultsThere was a statistically significant interaction between time and group for LF/HF from preseason (6.24 ± 5.77; 2.96 ± 1.81) to postseason (6.79 ± 6.75; 1.90 ± 1.02) in the low and high header groups, respectively (p=.024, partial h2=0.313). There were no other statistically significant changes in HRV for any other time or frequency domain outcome measure.ConclusionOur preliminary findings indicate that the LF/HF in the high header group differed from the low header group over the course of a soccer season. This may indicate that an increased number of chronic head impacts might result in an imbalance between sympathetic and parasympathetic activity, which would signify an alteration in autonomic function. These preliminary results demonstrate that additional research is needed in order to further understand the effects of heading on ANS function.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ectonucleotidases in the Hypothalamus of Salt‐Induced Hypertensive Rats: Transcriptional Profile and functional implications
Authors: Sá Renato Willian Martins , Ribeiro Natália , Ribeiro Luciene Maria , Mendonça Johnny Mendes , Santos Karol Martins , Antunes Vagner Roberto 
Published: June 2021

Ectonucleotidases consist of families of nucleotide metabolizing enzymes that hydrolyze extracellular nucleotides, such as ATP, to nucleosides. At the CNS level, these enzymes can affect the excitability of hypothalamic neurons by controlling the extracellular availability of ATP and adenosine. ATP, acting on P2 receptor in the PVN neurons, is involved in hyperosmolality‐induced sympathoexcitation and hypertension in rats. Therefore, we hypothesized that elevated sympathetic activity in salt‐induced hypertensive rats occurs in parallel to a suppression of ectonucleotidases gene expression at the PVN that failure to breakdown ATP. To test this hypothesis, we have used 2 cohorts of male Wistar rats: control (C; tap water; n=5) and salt‐loaded with hypertonic solution (HS; NaCl 2%; n=7) in replacement of the tap water for 7 days. The arterial blood pressure (ABP) was monitored 24‐hour by day during the 7 days via telemetry system. Low frequency (LF) component of systolic ABP (SBP) variability was measured by spectral analysis. PVN mRNA levels for E‐NTPDase1–3 and TMPAP were quantified using real time qPCR. All experimental procedures were approved by the ethical committee for animal research of the ICB‐USP (n° 38/2016). After 7 days of high‐salt intake the ABP of the HS group was higher (129±3 mmHg, p<0.05) compared to the C group (104±3 mmHg). The LF of SBP variability was higher in HS compared to C group [(1.33±0.23 mmHg2 (C) and 4.36±1.22 mmHg2 (LF)]. mRNA level for E‐NTPDase3 was higher in HS than in C group (3,09±0,6 ΔΔCt vs 0,99±0,5 ΔΔCt, respectively), and TMPAP expression was very low in HS group. mRNA levels of the E‐NTPDase1,2 did not differ between the groups. The data indicate that high expression of E‐NTPDase3 mRNA may be correlated to a greater ATP breakdown at PVN level of salt‐induced hypertensive rats.Support or Funding InformationFinancial support: FAPESP #2016/21991‐3 #2016/03359‐8; CAPESThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ionotropic Glutamate Receptors in the Paraventricular Nucleus (PVN) are Required to Trigger, but not Sustain, Sympathoexcitation by TNF alpha
Authors: MOURAO ALINE A. , SHIMOURA CAROLINE G. , PEDRINO GUSTAVO R. , TONEY GLENN M. 
Published: June 2021

In the hypothalamic PVN, pro‐inflammatory cytokines (PIC) have been implicated in driving sympathetic nerve activity (SNA) in support of neurogenic hypertension. In other brain regions, tumor necrosis factor alpha (TNF‐a), a prototypical early onset PIC, has been reported to enhance glutamatergic neurotransmission by increasing membrane trafficking and expression of postsynaptic AMPA receptors leading to synaptic long‐term potentiation (LTP). Here, we tested if TNFa triggers such a response in the PVN to increase SNA. In anesthetized male rats (n=5), unilateral PVN injection (50 nl) of aCSF vehicle had no effect on splanchnic SNA (+2 ± 0.6 %), but rat recombinant TNFa (0.6 pmol) injected 10 minutes later elicited a progressive, ramp increase that averaged 52 ± 2 % (p<0.001, n=5). In separate rats (n=3), injection of TNFa after an Emax dose of the AMPA receptor antagonist NBQX (5.2 nmol) increased SNA by only 11 ± 1 %, which was significantly less than the control response (p<0.001). Because AMPA receptor‐mediated membrane potential depolarization can relieve Mg2+ block of NMDA receptors to potentiate postsynaptic responses to AMPA receptor activation, the effect of NMDA receptor blockade with an Emax dose of AP5 (24 nmol) was tested in another group of rats (n=3). TNFα after AP5 increased SNA by 19 ± 3 %, which was significantly less than the response following vehicle and not different from that following NBQX. Results indicate that AMPA and NMDA receptors in the PVN each participate in the TNFα‐induced increase of splanchnic SNA. Of note, neither NBQX or AP5 injection 30 minutes after TNFα altered the ramp‐like increase of SNA. Mechanisms that sustain progressive sympathoexcitation in response to TNFα in the PVN remain to be determined.Support or Funding InformationCapes (AAM, GRP), NIH HL088052 & AHA 25710176 (GMT)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Augmented Vascular α1‐Adrenergic Receptor Sensitivity in Humans with Chronic Kidney Disease
Authors: Morison Doree Gardner , Li Yunxiao , Fonkoue Ida , Kankam Melanie , DaCosta Dana , Rapista Derick , Downey Ryan M. , Park Jeanie 
Published: June 2021

Patients with chronic kidney disease (CKD) have sympathetic overactivity and difficult‐to‐control hypertension. CKD patients also have exercise‐induced hypertension contributing to poor physical capacity. Our previous studies showed that CKD patients have augmented increases in blood pressure in response to the same degree of sympathetic activation during exercise, suggesting heightened neurovascular transduction of sympathetic nerve activity. We hypothesized that augmented vascular α1‐adrenergic receptor (α1‐AR) sensitivity contributes to the exaggerated vasoconstriction and blood pressure responses to sympathetic activation in CKD. In 28 CKD (Stage III and IV) patients and 11 matched Controls, we measured the degree of vasoconstriction of a dorsal hand vein in response to serial infusions of 10 doses (ranging 15–12,000 ng/min) of the selective α1‐AR agonist phenylephrine (PE) using a linear variable differential transformer with a movable central core to detect changes in vascular diameter. Vascular diameters were expressed as a % reduction from baseline maximum dilation, and plotted against PE dose concentrations in individual semi‐logarithmic dose‐response curves, and analyzed using a 5‐variable sigmoid dose‐response model. The natural log (ln) PE dose that produced a 50% maximal constriction (ED50) was calculated to reflect sensitivity to PE (i.e. α1‐AR sensitivity). CKD patients had a significantly lower PE ED50 compared to Controls (ln PE dose 5.15±0.30 vs 6.68±0.64 ng/min, p=0.022), demonstrating that CKD patients have heightened vasoconstriction in response to vascular α1 AR activation. CKD patients also had a significantly greater change in systolic blood pressure (SBP) during rhythmic hand grip exercise performed at 20% of maximum voluntary contraction compared to Controls (SBP +20.18±2.7 vs +10.43±1.74 mmHg, p=0.01), suggesting that augmented vascular α1‐AR sensitivity may contribute to increased neurovascular transduction and heightened exercise pressor responses in CKD. There was also a trend towards a positive linear correlation between estimated glomerular filtration rate (eGFR) and PE ED50. Augmented vascular α1‐AR sensitivity may contribute to increased neurovascular transduction and hypertension in CKD patients.Support or Funding InformationSupported by NIH HL‐098744, VA Merit I01CX001065, American Heart Association 15CSA24340001This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The caffeine effects on rotenone‐induced Parkinson's disease model in vitro and in vivo
Authors: Liu Tzu‐Hsien , Luo Chi‐Lun , Huang Bin , Lu Tzong‐Shi , Fu Yaw‐Syan 
Published: June 2021

Introduction and hypothesisThe degeneration and lost on dopaminergic neurons in midbrain may cause Parkinson's disease, and it is one of the most common neurodegenerative disease in human. Rotenone is a natural lipophilic toxic compound that is easy to cross the blood‐brain barrier, and widely used as insecticide and pesticide. Rotenone may impair mitochondrial oxidative phosphorylation and lead to dopaminergic neuron loss. In this study we investigated the protective effects of caffeine on rotenone‐induced Parkinson's disease models in vitro and in vivo.MethodsIn vitro, the dopaminergic cell line, SH‐SY5Y cells, is pretreated with caffeine (0~100 mM) for 30 mins and followed by treatment with rotenone (0~10 mM) for 1 hr~24 hr respectively. The cell survival rate, proliferation and morphology were analysis by flow cytometry, ELISA, Cell Counting Kit‐8(CCK‐8) and histology studies. Cell apoptosis/necrosis were analyzed by Annexin‐V/PI staining using flow cytometry. In vivo, the SD rats pretreated with caffeine (10 mg/kg daily, P.O.) or saline and followed treated with rotenone (1 mg/kg daily for 1 week, S.C.). The expressions of apoptosis and autophagy related proteins were analyzed by western blotting. The locomotion of rats were carried out by open field tests.ResultsCaffeine treatments (0–100 mM) had rarely toxic effect on SH‐SY5Y cell lines but could promote autophagy. The SH‐SY5Y cells treated with 1 nM rotenone for 8 hr may decrease the mitochondrial activity of around 60%. Pretreated with caffeine (>2 mM) for 30 min and followed treated with 10 nM rotenone for 8 hr could significantly increase total cell numbers and decrease the cell apoptotic ratio, but no effect on the necrosis ratio and did not restore the mitochondrial activity on rotenone‐induced dopaminergic cell toxicity. The locomotion of SD rats that pretreated with caffeine was better than the saline control in rotenone‐induced Parkinson's disease model. After exposure to rotenone, the situation of recovery by bradykinesia in daily caffeine‐treated group is more obviously than saline control.ConclusionsIn rotenone‐induced Parkinson's disease model, caffeine could facilitate autophagy, increase cell viability and animal locomotion. Our results indicated that caffeine has the potential protective effects on rotenone‐induced Parkinson's disease model.Support or Funding InformationKMU‐TP105E37This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Selective degradation of BET proteins with dBET1 attenuates lipopolysaccharide‐induced pro‐inflammatory response in microglia
Authors: Castro‐Rivera Carolina Isabelle , Yang Changjun Castro , DeMars Kelly M. , Candelario‐Jalil Eduardo Castro 
Published: June 2021

Stroke is the fifth leading cause of death in the United States and its most common type, ischemic stroke, is caused when a major blood vessel that carries oxygen and nutrients to the brain is blocked. This blockage initiates tissue death downstream resulting in inflammation and oxidative stress. Several studies have shown that microglia/macrophage neuroinflammatory responses significantly contribute to neuronal death in ischemic stroke. Bromodomain and extraterminal (BET) proteins‐ Brd2, Brd3, Brd4, and Brdt‐ bind to acetylated lysines on histones and act as a scaffold for transcription factors of several pro‐inflammatory genes important for the spread of cell death after stroke. To recreate the inflammatory process that occurs in response to ischemic stroke in vitro we subjected mouse SIM‐A9 microglia to lipopolysaccharide (LPS) stimulation and then treated with dBET1, a proteolysis‐targeting chimera (PROTAC) molecule that produces a targeted degradation of BET proteins. dBET1 is also a hybrid of the highly selective BET inhibitor, JQ1, that blocks the acetylated lysine‐binding pocket of BET proteins, complexed to a ligand for an E3 ubiquitin ligase. The PROTAC approach results in ubiquitination and subsequent degradation of the target protein by the proteasome. In this study, we did a dose‐response and a time course curve and found that 24 hours of treatment with 1 μM of dBET1 optimally decreases Brd2 and Brd4. Using Western blot and qRT‐PCR, we also found that treatment with dBET1 produced a dramatic reduction in the levels of inducible nitric oxide synthase (iNOS), cyclooxygenase‐2 (COX‐2), interleukin (IL)‐1β, tumor necrosis factor‐α (TNFα), IL‐6, chemokine ligand 2 (CCL‐2), and matrix metalloproteinase 9 (MMP‐9). This is the first study showing that dBET1‐mediated targeted degradation of BET proteins prevents pro‐inflammatory responses in LPS‐stimulated microglia. The data collected in vitro show promising results that suggest that in vivo studies using dBET1 may reduce the deleterious effects of stroke.Support or Funding InformationThis project was possible through the funding of the Neuroscience Summer Internship Program from the McKnight Brain Institute at the University of Florida. It also received funding through the University of Puerto Rico at Mayagüez's MARC U*STAR Program and the National Institutes of Health's grant 2T34GM008419‐26.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Differential subregional hippocampal expression patterns of microRNA‐338 and downstream target INSM1 following global cerebral ischemia.
Authors: Griffiths Brian B. , Ouyang Yi‐Bing , Giffard Rona , Stary Creed 
Published: June 2021

Cognitive dysfunction remains a devastating outcome in survivors of cardiac arrest. The principle source of cognitive impairment is attributed to delayed death of hippocampal cornu ammonis 1 (CA1) neurons following blood loss to the brain. Treatments that directly target CA1 neurons have not had translational clinical success. Astrocytes regulate the survival of CA1 neurons following injury, and treatments targeting astrocytes have been effective in protection from global cerebral ischemia. MicroRNAs (miRs) are non‐coding RNAs that regulate gene expression at the post‐transcriptional level, and modulation of miRs have been shown to augment survivability of hippocampal astrocytes. We identified miR‐338, a known modulator of astrocyte function, as a potential regulator of the transcriptional repressor INSM1, a critical epigenetic regulator of cell fate. To test the hypothesis that miR‐338 regulates astrocyte‐mediated neuronal survival following global cerebral ischemia by targeting INSM1, we assessed hippocampal subregional expression patterns of INSM1 and miR‐338 following global cerebral ischemia. We observed that prior to injury, INSM1 is highly expressed in the ischemia‐resistant dentate gyrus relative to the ischemia‐sensitive CA1. Following global cerebral ischemia, expression of INSM1 in the CA1 progressively increased, equaling DG expression after 7 days. We confirmed that increased expression in the CA1 was localized to astrocytes. Immediate future experiments will assess CA1 survivability and cognitive behavioral outcomes following miR‐338 inhibition in vivo.Support or Funding InformationRona Giffard NIH #5R01NS053898, Creed Stary AHA #14FTF19970029This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.