bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human placental derived stem cells protection in stroke injury.
Authors: Cananzi Sergio Giuseppe , Barzegar Mansoureh , Wang Yuping , Minegar Alireza , Boyer Christen , Knowles Kurt , Alexander Jonathan Steven 
Published: June 2021

Although stroke remains the 2nd leading cause of mortality with disastrous effects on long‐term disability in adults, there are few effective therapeutic approaches which can reduce post‐ischemic brain injury and neurological defects. Recently, stem cell‐based therapies for stroke have been shown to be neuroprotective and neurorestorative. Since stroke is a non‐progressive neurological disease, stem cell therapy would be an ideal approach to limit inflammation, suppress injurious immune mechanisms and stimulation of endogenous repair processes. In this study, we are using placental derived stem cells (hPDSC) as a treatment for brain damage following ischemia/reperfusion. The objective of this study was to determine the therapeutic potential of hPDSC in the treatment of post‐ischemic brain injury after a stroke event. Our central hypothesis is that hPDSC will decrease brain damage following cerebral ischemia/reperfusion by reducing immune system activation and infiltration, oxidative stress, and enhancing survival pathways. We measured infarct size and neurological scores on Sprague‐Dawley rats using a 2h middle cerebral artery occlusion (MCAO) model of stroke injury in adult rats. We found that intra‐arterial administration of hPDSC (1×10^6/0.3 ml) at the time of reperfusion significantly reduced infarct size from 49.8±18.7% (MCAO/HBSS) to 12.9±6.3% (MCAO/hPDSC), p=0.003 (comparing ipsilateral to contralateral hemispheres). Similarly, neurological scores were improved from 12.4±1.51 (MCAO/HBSS) to 18.8±2.48 (MCAO/hPDSC) p=0.0012(Garcia scale). Although the mechanistic basis of protection is still not completely clear, hPDSC improvements seem to reflect sparing of the cortex; less protection appears to be seen in the caudate. This cortical protection was also associated with improvements in tissue histopathology characterized by reduced necrosis and vacuolization with apparent preservation of oligodendrocytes. Our findings demonstrate that acute intra‐arterial administration of hPDSCs during reperfusion can significantly improves stroke outcomes at 24h. Future studies to evaluate timing, cell dosing and the cellular/molecular mechanisms underlying their beneficial actions may even further improve overall outcomes in this form of stem cell therapy. These studies will help fill a void in our understanding of the influence of hPDSC on cerebral blood vessels and how these factors may reduce brain damage following a stroke event.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
EFFECTS OF AEROBIC EXERCISE ON ISOPROTERENOL‐INDUCED CARDIAC DAMAGED RATS ASSOCIATED WITH BRAIN FUNCTIONS
Authors: Toth Kata , Nyakas Csaba , van der Zee Eddy A. , Schoemaker Regien G. 
Published: June 2021

BackgroundA bidirectional relationship was found between myocardial infarction (MI) and depression in patients, while comorbidity worsens prognosis. Alterations in neuroimmune processes are suspected to play a role in this interaction. Exercise has been shown to be beneficial for both conditions separately. Moreover, exercise has been indicated to have anti‐inflammatory effects. Aim of this study is to investigate whether isoproterenol‐induced cardiac damage is leading to neuroinflammation, behavioral and cognitive changes; and whether exercise can affect these parameters.MethodsFemale Wistar rats (11 months) were injected with either isoproterenol hydrochloride (ISO); a nonselective beta‐adrenoceptor agonist (70 mg/kg) or saline s.c. on two consecutive days, and allowed to recover for 2 weeks. Then groups were divided into sedentary and exercise subgroups, the latter undergoing 4 weeks of moderate intensity treadmill running. Cardiac function was assessed with echocardiography. Depressive‐like behavior was measured by open field (OF), while cognitive function was obtained from novel location (NL) and novel object (NO) recognition tests. Neuroinflammation was examined immunohistochemically by microglia activation, calculated as cell body to cell size ratio in IBA‐1 stained sections.ResultsCardiac dysfunction after ISO injection was confirmed by lower ejection fraction (EF; 72±1% in ISO vs 76±1% in saline rats), with no significant effect of exercise. Exercise tended to decrease depressive‐like behavior in the OF (% time in center: sedentary 7.8±1.8%; runners 13.1±1.9%; p=0.065). No significant effect of ISO on cognitive performance could be observed. ISO significantly decreased microglia activity by increasing dendrite area at similar cell body area (cell body/cell size 6.0±0.4 vs 7.6±0.4%) in the hippocampus CA1 area. Exercise had no significant effect on cognition or microglia morphology.ConclusionsCardiac dysfunction after repeated ISO injection in female rats reduced hippocampal microglial activation by increasing dendrite area. This may indicate alternative activation, associated with tissue protective properties. However, these immune changes were not associated with differences in behavior. Continuous aerobic exercise may increase exploration of the center of the OF, suggesting reduced anxiety.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Acute Exercise and Brain BACE1 Protein Content: a Time Course Study
Authors: Yang Alex J. , Hayward Grant C. , MacPherson Rebecca EK. 
Published: June 2021

Obesity and type 2 diabetes are significant risk factors in the development of neurodegenerative disorders, such as Alzheimer's disease (AD). A variety of cellular mechanisms, such as altered insulin and stress‐signaling contribute to neurodegeneration, and have been linked to increases in beta‐site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 is the rate limiting enzyme in the production of amyloid‐beta peptides which are implicated in the pathology of AD. Previous work suggests that a single, acute bout of exercise may have beneficial neuro‐protective effects in the prefrontal cortex of obese mice, independent of weight loss. The purpose of this study was to examine‐ how long the exercise induced alterations in the prefrontal cortex persist following a single exercise bout. Male C57BL/6 mice were fed either a low (LFD, 10% kcals from lard) or a high fat diet (HFD, 60% kcals from lard) for 7 weeks. HFD mice then underwent an acute bout of exercise (treadmill running: 15 m/min, 5% incline, 120 min) followed by a recovery period of 2, 8, or 24 hours. The HFD resulted in increased body mass (LFD 27.8±1.05 vs HFD 41.7±0.60 g; p<0.05) and glucose intolerance (AUC LFD 63.27±4.5 vs HFD 128.9±4.6; p<0.05). In the prefrontal cortex, BACE1 protein content was reduced 2‐ and 8‐hours post‐exercise compared to the sedentary HFD group, however BACE1 protein content 24‐hours post‐exercise was not different (p<0.05). Compared to the LFD, the HFD had higher prefrontal cortex phosphorylation of p38, JNK, and Akt (Ser473), with no changes in ERK phosphorylation, indicative of increased neuronal stress and aberrant insulin signaling. Post‐exercise p38 and JNK phosphorylation were no different from either the HFD or LFD groups, while ERK phosphorylation was significantly reduced by 24‐hours of recovery. These changes were accompanied by an increase in circulating BDNF (pg/ml) at 24‐hour recovery (p<0.01). Our results suggest that a single, acute bout of exercise may have beneficial neuro‐protective effects in obesity. We provide evidence that an acute bout of exercise can reduce markers of stress‐signaling pathways as well as BACE1 protein content in the prefrontal cortex. However, the reduction in BACE1 content is short lived and highlights the importance of daily exercise interventions for long‐term improvements in early AD‐associated pathology.Support or Funding InformationSupported by Alzheimer Society of Brant, Haldimand, Norfolk, Hamilton, and Halton PI:REKMThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Leptin Stabilizes Breathing but does not affect CO2 Chemosensitivity in Newborn Rat Pups
Authors: Hostovsky Liran Tamir , Ivanovska Julijana , Belik Jaques , Montadon Gaspard , Gauda Estelle B. 
Published: June 2021

Premature infants have periodic breathing (PB) and chronic intermittent hypoxia (CIH) that increases during the 2nd week of life. Leptin (LEP) is a hormone produced by adipocytes and increases central CO2 chemoreceptors sensitivity. LEP is also produced by the placenta, and in newborn infants LEP levels are highest at birth and then rapidly fall. We hypothesis that the fall in LEP after birth is associated with the increase frequency of PB and apnea leading to CIH during the 2nd week of life in premature infants.ObjectiveTo determine the effect of exogenous LEP on breathing stability and CO2 sensitivity during the first week of postnatal life, using whole body flow‐through plethysmograph in freely behaving newborn rats.MethodsSprague Dawley (SD) rat pups remained with the nursing dam until the time of the experiment. On postnatal day (PD) 7, rat pups were injected intraperitoneally with either vehicle (saline/n=5), LEP6 (6 μg/gr/n=4) and LEP9 (9 μg/gr/n=5). After injection the pup was returned to nursing dam and litter mates for 30 mins followed by 30 mins in the plethysmograph prior to recording. Respiratory tracings were captured using PowerLab 8 data acquisition system (ADInstruments) and analyzed using LabChart. Ventilatory parameters; frequency, VT and Ve were compared during 21% O2, 40% O2/0% CO2, 40%O2/5%CO2 and return to 40%O2/0%CO2, and the coefficient of variation (CV) for Ve was calculated for each condition in the 3 treatment groups (SAL, LEP6, LEP9).ResultsSimilar to Stunden et al. in rat pups at PD 7–8 (Stunden et al,, Respir Physiol, 2001), frequency, VT and Ve did not significantly changed in response to hypercapnia (P=0.511), and LEP6 or LEP9 did not alter this response. However, LEP exposure did stabilize breathing with a reduction in the CV during 21%O2, 40%O2/0%CO2 and 40%O2/5%CO2 (Figure 1).ConclusionOur preliminary findings are consistent with that of Stunden et al, who reported no change in Ve in response to hypercapnia at PD 6–8 in SD rats. At this age, the hypothalamus is insensitive to the effect of leptin on feeding and metabolism (MacKay H et al., Mol Metab. 2014). Here we show that leptin does not induce nor augment CO2 chemosensitivity in newborn rats at PD7, but does at PD 18 (Gauda et al, unpublished data), and adults (Isono S et al., Anesthesiology, 2009). However our data does show that leptin stabilizes breathing during the first week of life in newborn rat pups. We speculate that unstable breathing that occurs in premature infants may be associated with the precipitous fall in leptin levels after birth.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mechanism of Absorption and Transportation of Ovotransferrin in the Intestine
Authors: Shirkhani Rebin (Mohammad) , Lee Eun Joo , Talukder Jamil 
Published: June 2021

BackgroundOvotransferrin (OTF) is an iron‐binding protein present in eggs. It belongs to the transferrin family and shows sequence‐homology with mammalian transferrin and lactoferrin. This protein has been demonstrated to possess bioactive characteristics such as delivering iron to cells and inhibiting bacterial multiplication. However, the absorption and transportation of OTF through the intestinal epithelial cells remained unknown.AimsThe objectives of this study were to determine the absorption and transportation mechanism of OTF through rat intestinal epithelial cells (IEC‐6).MethodsIEC‐6 monolayer cells were grown on 6‐well transwell membrane with DMEM, bovine fetal serum, β‐hydroxybutyric acid, antibiotics, and insulin in a humidified CO2 incubator at 37°C. 10‐day post‐confluent cells were used for absorption and transport studies. OTF was loaded on the apical part and DPBS was collected from the bottom at 30 min at room temperature. Trans‐epithelial transport of OTF was initially detected by SDS‐PAGE with a molecular weight of 78 kDa. In order to carry out the real‐time uptake and transcytosis of OTF, 1 mg OTF/ml of DPBS was loaded and DPBS was collected from the bottom at different time intervals. Finally, the amount of OTF transported through the IEC‐6 cells following internalization was quantified by ELISA.Results and ConclusionThe OTF destined to the cell membrane and internalized was visualized by immunofluorescent and laser confocal microscopy. Microscopic images clearly showed the accumulation of OTF on the cell membrane provided the evidence of OTF‐receptors' presence on the plasma membrane. Also, OTF was detected within the cytoplasm of IEC‐6 cells, revealed that it was internalized by receptor‐mediated endocytosis. ELISA results demonstrated that OTF can be taken up by IEC‐6 cells as an intact protein from the apical surface and transported to the basolateral surface through trans‐epithelial exocytosis mechanism. The maximum internalization and exocytosis were observed at 90 min. These processes were time and concentration dependent, as the transferrin and lactoferrin do. Therefore, it is concluded that absorption and trans‐epithelial transportation of OTF accomplished by receptor‐mediated transcytosis in intestinal epithelial cells.
The Nedd8 Co‐E3 DCNL4 is regulated by dietary potassium in renal intercalated cells and promotes WNK kinase degradation via the KLHL3/CUL3 complex
Authors: Nkashama Lubika J. , Roy Ankita , Carrisoza‐Gaytan Rolando , Ray Evan C. , Marciszyn Allison , Kleyman Thomas R. , Satlin Lisa M. , Subramanya Arohan R. 
Published: June 2021

WNK kinases regulate NaCl and K+ transport in the distal nephron. The abundance of these kinases is controlled by the KLHL3/CUL3 complex, a cullin‐RING E3 ligase (CRL) that ubiquitylates the WNKs, marking them for degradation. Little is known about the mechanisms that physiologically regulate KLHL3/CUL3 complex activity. Mammalian DCN‐like (DCNL) proteins are a family of five evolutionarily conserved “co‐E3s” that promote CRL activation via neddylation. Since DCNL proteins are required for CRL activation in vitro, we hypothesized that specific DCNLs might be localized to the distal nephron to downregulate WNK kinases via the KLHL3/CUL3 complex. A kidney RNAseq database (Lee JW JASN 2015) detected DCNL4 transcripts in microdissected distal nephron segments, particularly the connecting tubule and cortical collecting duct. In immunohistochemistry and immunofluorescence studies, DCNL4‐specific antibodies detected a strong cytoplasmic signal in distal nephron intercalated cells (ICs). Notably, the signal was absent in the distal convoluted tubule and loop of Henle, the classical sites of WNK pathway activity. Recently, we showed that the abundance of the “long” kinase active form of WNK1 (L‐WNK1) is increased in ICs during dietary potassium loading. Consistent with this finding, dietary potassium loading (5% K+ with mixed citrate chloride and carbonate x10d) increased the abundance of the L‐WNK1 effector kinase SPAK in ICs, and decreased the abundance of DCNL4 by 53% by immunoblotting. Conversely, 10d of dietary K+ restriction upregulated DCNL4 in ICs and reciprocally decreased the abundance of L‐WNK1. In 293 cells, dicer substrate RNA‐mediated knockdown of DCNL4 increased endogenous steady state L‐WNK1 abundance, while overexpression of DCNL4 in the presence of KLHL3 and CUL3 enhanced L‐WNK1 degradation. These data support a model in which DCNL4 functions as an IC‐specific brake that downregulates L‐WNK1 and SPAK activity during hypokalemia, a process that is released during dietary potassium loading to activate IC‐mediated K‐secretion, possibly via basolateral NKCC1 cotransporters and apical BK channels. Thus, these findings suggest a novel physiological role for a specific DCNL protein in the regulation of potassium homeostasis.Support or Funding InformationNIH R01DK098145, R01DK038470, P30DK079307This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Copper supplementation in drinking water reverses dietary iron overload‐induced anemia and cardiac hypertrophy in mice
Authors: Wang Tao , Xiang Ping , Ha Jung‐Heun , Doguer Caglar , Wang Xiaoyu , Flores Shireen , Kang Y. James , Collins James F. 
Published: June 2021

Our previous studies showed that high‐iron (0.88% carbonyl iron) diet feeding of mice and rats lead to impaired growth, severe anemia, tissue copper depletion and cardiac hypertrophy.1,2 Interestingly, these pathophysiological perturbations were prevented by addition of extra copper to the high Fe diet, indicating the role of copper deficiency in the pathogenesis. The current study was undertaken to test the hypothesis that dietary copper supplementation to Fe overload mice could restore systemic copper status, and reverse the anemia and cardiac hypertrophy. Weanling, male C57BL/6 mice were fed AIN‐93G‐based diets containing adequate (~8 ppm) Cu in combination with adequate (~80 ppm) or high (~8000 ppm) Fe for 4 weeks. Then, the mice were given 20 mg/L Cu (as Cu sulfate) in drinking water for another 3 weeks. Subsequently, the iron and copper‐related phenotype of the mice was assessed. High‐Fe diet fed mice showed a significant growth impairment and systemic Cu deficiency, accompanied by severe anemia, decreased serum ceruloplamine (Cp) activity and cardiac hypertrophy. Cu replenishment via drinking water corrected the deficits in hemoglobin (Hb), hematocrit (HCT) and serum Cp levels, restored tissue Cu status, and reversed cardiac hypertrophy. It was further found that high‐Fe feeding significantly impaired intestinal Cu absorption, and disturbed Cu tissue distribution. This study demonstrates that high Fe consumption blocks intestinal Cu absorption, leading to a systemic Cu deficiency which resulted in a severe anemia and cardiac hypertrophy in mice. Cu supplementation corrects these physiologic perturbations. These observations provided further evidence of physiologically‐relevant iron‐copper interactions in mammals.Support or Funding InformationSupported by NIH grant 1R01 DK074867 (to J.F.C.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Induced Pluripotent Stem Cells (iPS)‐Derived Extracellular Vesicles Improves Immune Dysfunction and Attenuates Splenomegaly in Aged Mice
Authors: Ullah Mujib , Feng Rui , Sun Zhongjie 
Published: June 2021

Background and ObjectiveAging is associated with declined immune function and increased inflammatory responses. Secreted extracellular vesicles (EVs) are loaded with growth factors, cytokines, and miRNAs. The purpose of this study is to investigate the effect of intravenous delivery of iPS cell‐derived EVs on the aging‐associated immune dysfunction.Methods and ResultsThe iPS cell‐derived EVs was confirmed by the expression of CD9, CD63 and CD83. The populations of T and B lymphocytes were decreased in aged mice, indicating that aging impairs the immune function. Intravenous delivery of EVs rescued the aging‐related decrease in immune cell populations. The size and weight of spleens were increased in aged mice, suggesting that aging causes spleen hypertrophy (splenomegaly). We found that the aging‐related splenomegaly was accompanied by increased cell death, necrosis, unbalanced ratio of immune cells, and augmented inflammation. Immunosenescence, cell arrest, apoptosis, fibrosis and iron accumulation was also found in the hypertrophied spleens of aged mice. Interestingly, EVs significantly attenuated aging‐associated splenomegaly, immunosenescence, cell arrest, apoptosis, and spleen remodeling. Aging enhanced inflammation as evidenced by increased immune cells and proinflammatory cytokines (IL‐1β, IL‐18, TNF‐α) in aged mice. iPS cell‐derived EVs markedly reduced inflammation, improved population of B and T cells, and increased anti‐inflammatory cytokines (IL‐4, IL‐6, IL‐10, IL‐13, TGF‐β) in aged mice. In comparison with EVs alone, EVs overexpressing klotho protein (an antiaging protein) more effectively enhanced the immune function and suppressed inflammation in aged mice.ConclusionsThese results showed for the first time that EVs alone or in combination with klotho overexpression suppressed aging‐associated inflammation and splenocyte apoptosis likely via modulating the immune function. EVs may be a promising interventional strategy for aging‐related immune dysfunction and splenomegaly.Support or Funding InformationNIH R01 AG049780, HL118558, AND DK093403.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effect of SIRT1 Expression on Glucose Metabolism in Lean and Obese Mice
Authors: Marshall Kent L. , Bryner Randy W. , Pitzer Christopher , Drake Alexis , Myers Matthew , Mohamed Junaith , Alway Stephen E. 
Published: June 2021

BackgroundSirtuin‐1 (SIRT1) through its deacetylase activity, is involved in numerous cellular processes including metabolism, gene silencing, and cellular survival. Recently, SIRT1 has been shown to play an important role in glucose metabolism and glucose tolerance, in part through its effect on insulin secretion and peripheral insulin sensitivity. Less is known about the exact tissue location for SIRT1's primary role in regulating blood glucose. In addition, little is known about the role SIRT1 may play in regulating blood glucose following the induction of an obese phenotype. We hypothesized that global over‐expression of the SIRT1 gene, as compared to lack of expression in metabolically active tissue, would allow for efficacious and enhanced glucose tolerance following hyperglycemic insult in both lean and obese animals.MethodsThirty‐two 60–70‐week‐old male and female (C57 Bl‐6) mice were used in the study. Groups were as follows: wild type (WT; N=10), SIRT1 global over‐expressors (OE; N=11), SIRT1 skeletal muscle satellite cell knockout (SKO; N=5), and SIRT1 skeletal muscle cell knockout (MKO; N=6). All groups underwent a glucose tolerance test (GTT) by administering an intraperitoneal injection of glucose solution containing 1g/kg of glucose relative to bodyweight following an eight hour fast. The resulting blood glucose levels were measured using tail stick and a standard Bayer™ Contour® glucometer at baseline, and 15, 30, 60, 90, and 120 minutes post‐injection. Following a 10‐week high caloric feeding regimen, which resulted in significant weight gain, WT and OE mice were given a second GTT. Data were analyzed using a one‐way and two‐way ANOVA with STATVIEW with significance set at 0.05.ResultsAll measurements were determined to be independent of gender and weight. Initial fasting glucose levels were similar across all groups. Peak blood glucose was significantly lower in SKO (148±22 mg/dL) versus WT (207±21 mg/dL), OE (230 ± 10 mg/dl) and MKO (202 ± 12 mg/dl). The area under the glucose tolerance curves (AUC) was also significantly lower in SKO (652) versus WT (868), OE (895), and MKO (833). There was a significant interaction pre‐to‐post obesity between WT vs OE for AUC (WT‐pre: 868, WT‐post: 1108; OE‐pre: 895, OE‐post: 807).ConclusionSkeletal muscle satellite cell knockout of SIRT1 appeared to result in a better handling of glucose following IPGTT. Following 10 weeks of increased calorie consumption, resulting in significant weight gain, the OE group actually appeared to handle glucose better than WT litter‐mates.Support or Funding InformationThis project has been funded through grants from WV‐INBRE (NIH grant P20 GM103434) to the Genomics Core Facility and the WV Program to Stimulate Competitive Research (PSCoR)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.