bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phrenic Nerve and Carotid Body Responses to Hypoxia and CO2 in Naked Mole Rats
Authors: Wang Benjamin , Peng Ying‐Jie , Nanduri Jayasri , Wang Ning , Prabhakar Nanduri R , Pamenter Matthew 
Published: June 2021

Naked mole‐rats (NMRs), which live in underground burrows, are tolerant to hypoxia. In the present study, we examined the efferent phrenic nerve and carotid body (CB) responses to hypoxia and CO2 in NMRs and the results were compared with Bl6 mice. The phrenic nerve responses to 10% O2 and 10% CO2 for 3 min were examined in anesthetized animals. Stimulation of minute neural respiration (MNR = phrenic bursts/min × tidal phrenic amplitude) evoked by hypoxia was ~ 50% less, whereas by CO2 was ~200% higher in NMRs as compared to Bl6 mice. The magnitude of CB sensory nerve excitation for a given level of hypoxia was comparable, whereas the CB response to CO2 was ~100% higher in NMRs as compared with Bl6 mice. Morphological analysis of CB with anti‐chromogranin A (CGA, a synaptic vesicle marker) and anti‐tyrosine hydroxylase (TH; a glomus cell marker) antibodies showed a dispersed pattern of glomus cells in NMR CBs as compared with a clustered pattern in Bl6 CBs. These findings suggest that breathing and CB responses to hypoxia and CO2 differ between NMR and Bl6 mice and these effects are associated with striking differences in CB morphology.Support or Funding InformationSupported by NIH‐HLBI P01‐HL‐90554This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
H2S synthesis inhibitor prevents hypoxia‐evoked periodic breathing in spontaneous hypertensive rats
Authors: Zhang Xiuli , Peng Ying‐Jie , Nanduri Jayasri , Muzzio Miguel , McCormick David L , Prabhakar Nanduri R 
Published: June 2021

Hyperactive carotid body (CB)‐chemo reflex has been implicated in evoking periodic breathing (PB) characterized by episodes of hyperventilation and hypoventilation (decreased tidal volume and respiratory rate). Spontaneous hypertensive (SH) rats exhibit augmented CB response to hypoxia and this effect is mediated by increased H2S production from cystathionine‐g‐lyase (CSE; Peng et al. PNAS, 2017). In the present study, we examined whether acute hypoxia evokes PB in SH rats. Breathing was monitored in conscious SH rats (age 2–4 months old) by whole‐body plethysmography. Hypoxia evoked PB in SH rats in a stimulus‐dependent manner. Exposure to 12% O2 elicited 40 ± 3 episodes of PB/hr and severe hypoxia (8–10% O2) elicited 114 ± 4 episodes of PB/hr. Oral administration of L‐propargylglycine (L‐PAG), a CSE inhibitor, prevented CB hypersensitivity to hypoxia and stabilized breathing in dose‐related fashion. L‐PAG is rapidly absorbed after oral dosing (Tmax = 0.25 to 0.5 hr) and oral bioavailability is 100%. These data demonstrate that CSE inhibition provides a viable mechanism for prevention of breathing instability arising from CB hypersensitivity to hypoxia.Support or Funding InformationSupported by NHLBI grant UH3HL‐123610This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Induction of asthma causes sensitization of the carotid bodies to lysophosphatidic acid
Authors: Jendzjowsky Nicholas Gregory , Roy Arijit , Wilson Richard 
Published: June 2021

Previously, we demonstrated an important role for the carotid bodies in asthmatic bronchoconstriction. Specifically, we showed that an allergen‐induced increase in circulating lysophosphatidic acid (LPA) in asthmatic rats activates LPA receptors (LPAr) in the carotid bodies and post‐ganglionic TRPV1 channels, provoking vagal activity and thereby triggering acute bronchoconstriction (Jendzjowsky et al. 2018 Nat Comm. 9, 4030). Here we report that induction of asthma causes molecular and functional changes to the carotid bodies that sensitize them to LPA.Experiments were carried out using the standard ovalbumin‐sensitized brown Norway rat model of asthma. Carotid bodies and petrosal ganglia were extracted 3 hours after the third ovalbumin challenge in asthmatic (OVA) or third saline challenge in naïve (N) rats. Using qPCR (Δctt OVA vs N), LPAr expression was increased in the carotid body (LPAr1: 556x; LPAr2: 20x; LPAr3: 2x; LPAr4: 150x; LPAr5 only detected in OVA: LPAr6: 175x; TRPV1 not detected, as demonstrated previously Roy et al. 2012 J Appl Physiol 112:212–224) whereas LPAr 1–6 and TRPV1 were similarly expressed in petrosal ganglia of OVA and N rats. Using the perfused ex vivo carotid body preparation, baseline normalized carotid sinus nerve responses to increasing doses of LPA activity, were significantly augmented in OVA compared to N rats (2.5uM‐ OVA: 1.12 ± 0.01 N: 1.05 ± 0.02, p=0.162; 5uM: OVA: 1.23 ± 0.03 N:1.10 ± 0.02, p=0.009; 10uM: OVA: 1.40 ± 0.07 N: 1.17 ± 0.03, p<0.001). In contrast, carotid body activity in response to hypoxia was not different between OVA (2.54 ± 0.47) and N (1.95 ± 0.10) rats (p=0.243).Our data suggest that asthmatic carotid bodies have enhanced responsiveness to LPA, independent of hypoxic sensitivity. These changes likely contribute to the acute allergen‐induced bronchoconstriction which is the hallmark of asthma that appears to be mediated, in part, by a novel carotid body‐vagal‐lung neuronal pathway. Targeting carotid body LPA signalling may reduce asthmatic bronchoconstriction and provide new pharmaceutical targets for inflammatory lung disease.Support or Funding InformationThis project was funded by The Lung Association and Canadian Institute for Health Research.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ventilatory response to hypoxia and tolerance to high altitude in women: Influence of menstrual cycle, oral contraception and menopause
Authors: Richalet Jean‐Paul , Lhuissier François J , Jean Dominique 
Published: June 2021

Tolerance to high altitude in women might be influenced by hormonal status since female hormones are known to modulate ventilation. We explored the influence of 1) the phase of menstrual cycle, 2) oral contraception, 3) menopause with or without hormonal treatment, on ventilatory (HVRe) and cardiac (HCRe) responses to hypoxia at exercise in 1060 women prior to exposure at high altitude. HCRe and HVRe were measured during a routine hypoxia exercise test. Prevalence of Severe High Altitude Illness (SHAI) was assessed in a subgroup of 260 women. Four groups of women were defined: non‐menopaused with or without oral contraception; menopaused with or without hormonal treatment. In non‐menopaused women without contraception, HVRe was higher in the early luteal phase than in the early follicular phase (0.89±0.37 vs 0.75±0.27 ml/min/kg, p=0.03). HVRe was higher (p=0.016) and HCRe lower (p<0.001) in menopaused vs non‐menopaused women. Independently of hormonal status, HVRe decreased from second to fourth decade of age and increased from fourth to eighthdecade, while HCRe consistently decreased with ageing. Oral contraception or hormonal treatment had no effect on responses to hypoxia. The prevalence of SHAI was similar in all groups. SHAI prediction score was higher and HVRe lower in women with SHAI, without taking actetazolamide. In conclusion, 1) physiological responses to hypoxia depends on the ovarian cycle phase and on menopause status, 2) oral contraception, and hormonal treatment have no influence on response to hypoxia and tolerance to high altitude, 3) independently of hormonal status, ageing modulates physiological responses to hypoxia, 4) the optimal phase for high altitude acclimatization for women would be the early luteal phase.Support or Funding InformationAssociation pour la Recherche en Physiologie de l'EnvironnementThis 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, Sleep Fragmentation and Glucose Tolerance
Authors: Framnes‐DeBoer Sarah , Arble Deanna 
Published: June 2021

Obstructive sleep apnea is a common sleep disorder affecting 17% of the total population and characterized by repeated bouts of intermittent hypoxia and sleep fragmentation. Both intermittent hypoxia and sleep fragmentation are hypothesized to have independent consequences on cardiometabolic health. In the clinical setting, the ability to tease apart the relative contributions of intermittent hypoxia from sleep fragmentation is limited. Here, we use mice exposed to intermittent hypoxia either during their rest or active phase to systematically determine the metabolic effects of intermittent hypoxia + sleep fragmentation or intermittent hypoxia alone. We find that 9 hours of mild, intermittent hypoxia, (a 30‐second, 12% 02 event occurring once per minute) is sufficient to impact glucose metabolism when applied during the resting phase, but not during the active phase (AUC 16733 ±1326 vs 21189 ±1395, respectively, p < 0.05). However, only a more severe intermittent hypoxia protocol (a 30‐second, 7% 02 event occurring once per minute) was found to affect the glucose tolerance of both resting and awake mice (AUC: 17063 ± 1328 vs 17167 ±696, respectively). These data demonstrate that the severity of intermittent hypoxia dictates the glucose response in awake mice, while sleep fragmentation may chiefly influence the glucose metabolism of a resting mouse. Taken together, these results demonstrate distinctive and interdependent roles for intermittent hypoxia and sleep fragmentation on glucose metabolism.Support or Funding InformationDr. Arble receives funding from the American Heart Association (PI Arble, 17SDG33660108) and Marquette Biological Sciences Department.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hypoxia Inducible Factor Activation Prevents Renal Mitochondria Dysfunction and Improves Cortical Oxygenation in Type 1 Diabetic Mice
Authors: de Carvalho Carla Luisa Lopes , Schiffer Tomas , Zheng Xiao‐Wei , Grunler Jacob , Karlsson Susanne , Mazzone Massimiliano , Carmeliet Peter , Inagi Reiko , Hansell Peter , Catrina Sergiu‐Bogdan , Friederich‐Persson Malou , Palm Fredrik 
Published: June 2021

Hypoxia‐inducible factors (HIFs) are transcription factors that are activated during hypoxia in order to regulate a hypoxic gene response. During normoxia, prolyl hydroxylase domain‐containing protein 2 (PHD2) is one of three isoforms that acts on HIF as a first step towards its degradation and its knockdown consequently results in HIF activation. Previous studies have demonstrated that diabetes induces mitochondria dysfunction resulting in renal cortical hypoxia, yet studies indicate that hyperglycemia impairs HIF stabilization resulting in suboptimal activation and an inability to correct renal hypoxia. In this study, we hypothesize that increased HIF‐activation resulting from PHD2 knockdown, prevents mitochondria dysfunction and improves renal oxygenation in type 1 diabetic mice.Balb/c mice from four groups (Wild type normoglycemic (n=16), wild type diabetic (n=10), PHD2+/− normoglycemic (n=16) and PHD2+/− diabetic (n=11)) were placed in metabolic cages for 24 h urine collection followed by conscious determination glomerular filtration rate (GFR), using a single bolus injection of FITC‐inulin. Diabetes was induced by a low dose injection of strepzotocin (i.p.) for 5 consecutive days and diabetes duration was 5–6 weeks. Renal cortical oxygenation was measured with Clark electrodes and kidney mitochondria function, including mitochondria proton leak, was assessed by high resolution respirometry. Urinary excretion of albumin and thiobarbituric acid reactive species were measured and corrected for 24 h urine volume.Diabetes resulted in increased GFR in both groups compared to normoglycemic mice. Wild type diabetic mice presented with increased total mitochondrial leak respiration compared to normoglycemic mice, which was prevented in the PHD2+/− mice. Interestingly, regulated leak, defined as mitochondrial proton leak regulated by uncoupling proteins and adenosine nucleotide translocase, was increased in diabetic PHD2+/− only, while unregulated leak, defined as total leak minus regulated leak, was increased in wild type diabetic mice. Both diabetic groups displayed increased albuminuria and thiobarbituric acid reactive species compared to normoglycemic control mice.In conclusion, activation of HIF by reducing PHD2 expression prevents mitochondria dysfunction and renal cortical hypoxia in type 1 diabetic mice. This could imply a novel target for the PHD inhibitors currently in clinical trials.Support or Funding InformationThis study was supported financially by the Swedish Research Council, the Swedish Diabetes Foundation and the Family Ernfors Fund.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Glucosamine chronic treatment differently modulates uterine artery from pregnant and virgin Wistar rats
Authors: Justina Vanessa Dela , Webb R Clinton , Lima Victor Vitorino , Giachini Fernanda Regina 
Published: June 2021

BackgroundO‐linked β‐N‐acetylglucosamine (O‐GlcNAc) is a post‐translational modification that modulates several proteins related to the vascular tone control. Dysregulation of O‐GlcNAcylation occurs in a wide range of diseases, favoring endothelial dysfunction. During pregnancy, vascular dysfunction observed in the uterine vasculature results in inadequate nutritional support between the maternal‐fetal interface. It remains to be elucidated whether augmented O‐GlcNAc levels impact uterine artery (UA) function from virgin or pregnant rats.HypothesisIncreased O‐GlcNAc impairs the endothelial function of the uterine artery.MethodsPregnant or virgin Wistar rats (14‐week old) were treated either with glucosamine (300 mg/Kg) or vehicle, for 21 days, i.p. The UAs were rapidly removed, cleaned from fat tissue and mounted for isometric force development record. Concentration response‐curves to acetylcholine (1 nM to 100 μM) were performed in UA contracted with phenylephrine (10 μM), in the presence or absence of L‐NAME (100 μM, 30 minutes). Protein expression was evaluated by western blot.ResultsGlucosamine treatment increased O‐GlcNAc expression in UAs from virgin rats (p= 0.04). Decreased endothelium‐dependent relaxation was observed in UAs from treated virgin rats compared to vehicle [Emax 56.16 ± 4.18 vs. 76.38 ± 3.92%, respectively], which was abolished by incubation with L‐NAME. Endothelial nitric oxide synthase (eNOS) activity was decreased (p=0.04) by glucosamine‐treatment in virgin rats. On the other hand, in pregnancy, treatment with glucosamine decreased O‐GlcNAc expression (p=0.03) in UAs compared to vehicle. Increased sensitivity to acetylcholine [pD2 6.43 ± 0.13 vs. 6.90 ± 0.11] was observed in the UAs of glucosamine‐treated pregnant rats compared to vehicle pregnant rats with no differences in the maximal response. eNOS activity was unchanged between these groups.ConclusionsGlucosamine‐treatment impairs UA endothelial function in virgin, but not in pregnant rats.Support or Funding InformationCAPESFAPEGNIH (HL‐134604)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
In Vivo Effect of Luteolin during Oxaliplatin Treatment for Colorectal Cancer
Authors: Moon Nayoung , Jang Chan Ho , Averilla Janice Nullan , Jeong Soojung , Lim Ji Sun , Lo Jisun , Kim Jong‐Sang 
Published: June 2021

Phytochemicals that induce nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) can lower cellular oxidative stress and thus favor cell viability. Considering our previous in vitro study demonstrating that strong antioxidative called luteolin interfered with the anticancer effect of oxaliplatin on HCT116, we hypothesized that luteolin administration would be unadvantageous during oxaliplatin‐based chemotherapy. To test this hypothesis, HCT116 xenograft mouse model was established in BALB/c nude mice. Once palpable tumors were developed after HCT116 cells were subcutaneously transplanted on both flanks of each mouse, mice were randomly allocated into four groups that were intraperitoneally injected with (1) vehicle only (control), (2) oxaliplatin at a dose of 10 mg/kg body weight (BW), (3) luteolin at 50 mg/kg BW, or (4) combination of luteolin and oxaliplatin. Tumor size and body weight were regularly monitored (three times a week) for three weeks. Results demonstrated that oxaliplatin treatment inhibited the growth of xenografted tumors as expected, luteolin treatment had little effect on the tumor size, and combinatorial treatment of oxaliplatin and luteolin most suppressed tumor growth. In addition, oxaliplatin‐luteolin combo reduced heme oxygenase‐1 (HO‐1) protein expression compared to oxaliplatin alone. Moreover, luteolin alone treatment enhanced protein expressions of p53 and its downstream molecule p21. These findings were suggestive of in vivo synergistic effect of combinatorial treatment of oxaliplatin and luteolin at the tested doses in this study and the possible coordinated regulation via p53 and/or HO‐1‐mediated cytoprotection in HCT116 xenograft tumor growth. According to the current observations, our hypothesis ought to be reconsidered; luteolin could advantageously hamper tumor growth during oxaliplatin treatment in colon cancer.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Previous Adaptation Period Modulates Pregnancy Swimming Neuroprotective Effects on the Offspring Following Neonatal Hypoxic‐Ischemic Brain Injury
Authors: Tassinari Isadora Davila , Sanches Eduardo Farias , Fabres Rafael Bandeira , Andrade Mirella Kielek Galvan , Rodrigues Thais Lopes , Carvalho Andrey Soares , Rezena Ester , Mazeron Larissa Sagaz , Netto Carlos Alexandre , de Fraga Luciano Stürmer 
Published: June 2021

Neonatal hypoxic‐ischemic encephalopathy (HI) is one the main causes of neurological damage in newborns. Pregnancy has emerging as a feasible therapeutic window for preventing central nervous system damage and has been shown to decrease early and long‐term HI consequences. However, experimental literature is conflicting and point that variables, such as a previous adaptation period to the exercise (before mating) has decisive impact on swimming consequences to the injured offspring's brain.Briefly, the adaptation period consisted of exposing female rats to 7 days (with increasing time exposure ‐ from 5 to 20 minutes) to a tank (200 cm diameter) filled with water at 32°C. After mating, from gestational day 0 to 21, pregnant rats were submitted to 20min/day of swimming or remained in the standard cages. After birth, seven‐days‐old rats were subjected to the Levine‐Rice HI model (right common carotid artery occlusion followed by 8% O2/60min). Western blotting was used to assess protein expression of GFAP (astrocytic reactivity), cytochrome c and cleaved caspase 3 (apoptotic markers) was performed in hippocampus 24h after HI. Animals were divided into 8 experimental groups, according adaptation, swimming and. Behavioral analysis was performed from PND45 and included sensorimotor and cognitive testing. Histological analysis assessed structural brain damage volumes of hemisphere and hippocampus. This study was approved by the local Institutional Animal Care and Use Committee (UFRGS #33497)Non‐parametric tests showed significant increase in astrogliosis in non‐adapted HI animals only. Swimming decreased apoptotic cell death despite adaptation period. Cylinder test evidenced HI effects (increasing the use of the ipsilateral forepaw in HI animals). No effects of swimming nor adaptation were observed in the test. In the open field testing, only HI animals whose mothers where adapted previously to the injury had increased locomotion and swimming reversed the HI effects on the test. Hemisphere and hippocampus were preserved only in the HI group whose mothers swam and were adapted before mating. In summary, the adaptation period has a major role on pregnancy swimming effects following HI and must be considered in future studies and the mechanisms involved in such modulation need to be further explored.Support or Funding InformationThis study was supported by CNPq, FAPERGS and CAPES ‐ 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.
Notch1 Overexpression in Cardiac Mesenchymal Stem Cells Renders their Exosomes Highly Effective in Promoting Angiogenesis and Cardiac Regeneration
Authors: Xuan Wanling , Tang Yaoliang , Ashraf Muhammad 
Published: June 2021

ObjectiveNotch1 signaling is critical in postnatal angiogenesis. Cardiac mesenchymal stem cells (C‐MSC) are endogenous cardiac stromal cells which are believed to facilitate cardiac regeneration via paracrine effects. Here, we investigated the effects of exosomes from Notch1 engineered C‐MSC on angiogenesis and cardiac myocyte proliferation in ischemic myocardium.Methods and resultsC‐MSC were isolated from conditional Notch1 knock out mice. For Notch1 knockout C‐MSC generation, Notch1 gene was deleted via adenoviral vector mediated Cre recombination. For Notch1 overexpression, cells were modified with Notch1 intracellular domain (NICD). Myocardial infarction (MI) mouse model was generated by LAD ligation. Exosomes from C‐MSC (Exo‐C‐MSC), Notch1 knockout C‐MSC (Exo‐C‐MSCNICD KO) and Notch1 overexpressing C‐MSC (Exo‐C‐MSCNICD) were isolated and characterized. Both Exo‐C‐MSC and Exo‐C‐MSCNICD were strongly pro‐angiogenic under in vitro and in vivo conditions. Compared with Exo‐C‐MSC, Exo‐C‐MSCNICD treatment led to dense tube formation and higher vessel density in peri‐infarct area. Moreover, knockout of Notch1 significantly abrogated the pro‐angiogenetic effect of Exo‐C‐MSC. Compared with control group, pretreatment of Exo‐C‐MSC and Exo‐C‐MSCNICD also exerted anti‐apoptotic effects on endothelial cells stressed with 300 μM H2O2, for 8h. Exo‐C‐MSCNICD KO had no anti‐apoptotic effect in H202 treated cells. As expected, intramyocardial injection of Exo‐C‐MSCNICD were strongly cardioprotective on cardiomyocytes (CMs) and vessel cells 24h after MI. Though both Exo‐C‐MSC and Exo‐C‐MSCNICD treatment improved cardiac function and decreased fibrosis in mice one‐month post‐MI, Exo‐C‐MSCNICD were more effective in improving cardiac function and reducing fibrosis. On the other hand, Exo from Notch1 knockout MSC had no effects on fibrosis or function. A significant effect on vessel density and CMs proliferation (ki67 and α‐actinin double positive cells) in peri infarct area was observed with the treatment of Exo‐C‐MSCNICD in comparison with PBS, Exo‐C‐MSC and Exo‐C‐MSCNICD KO groups.ConclusionNotch1 overexpression in C‐MSC produced highly effective exosomes in preventing cell death, promoting angiogenesis, cardiomyocyte proliferation and in restoring cardiac function after MI. These data suggest that Notch1 activation may further enhance the effectiveness of exosomes from C‐MSC in cell‐free therapy.Support or Funding InformationR01 HL134354 and R01 AR070029This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.