bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protective Effect of Oxytocin Against Apoptosis and Oxidative Stress: Role of Extracellular Signal Regulating Kinases
Authors: Havranek Tomas , Alanazi Mohammed M. , Bakos Jan , Bacova Zuzana , Cubeddu Luigi X. , Castejon Ana Maria 
Published: June 2021

Neuropeptide oxytocin plays a role in the neuronal proliferation, differentiation and affects related morphological changes of neuronal cells. It has been suggested that oxytocin has protective effect against inflammation and consequences of oxidative stress. However, mechanisms of its action at the molecular level are not fully understood. The aim of the present study was to determine oxytocin anti‐apoptotic effects and potential inhibition of oxidative stress in glioblastoma U87‐MG cell line. We have clearly shown that activation of oxytocin receptors dose‐dependently stimulated proliferation of U‐87MG cells. Incubation of cells in the presence of oxytocin increased ERK1/2 phosphorylation, which was reduced by oxytocin receptor antagonist. Our results also revealed that in the U87‐MG cell‐line, hydrogen peroxide (H2O2) increased the intracellular reactive oxygen species (ROS) production in a dose‐dependent manner. Interestingly, cells treated with H2O2 in the presence of oxytocin showed a significant decline in the ROS production. We have also confirmed that oxytocin mediates its protective effect in U87‐MG cells through activation of the MAPK/ERK ½ signaling pathway. The protective effect of oxytocin has been observed against consequences of oxidative stress in peroxide model and apoptosis induced by camptothecin, as well. To our best knowledge this is the first study demonstrating that there is interference in production of ROS and activation of oxytocin receptors in neuronal cells. Overall, the present data indicate that oxytocin stimulates proliferation and protects glial cells against apoptosis and oxidative stress.Support or Funding Information1‐ President's Faculty Research & Development (PFRDG) Grant ‐ 2015–20162‐ Saudi Arabian Cultural Mission (SACM) Graduate Students Research GrantThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mathematical model of megalin trafficking in differentiated proximal tubule cells and its application in Dent disease
Authors: Shipman Katherine , Long Kimberly R , Rbaibi Youssef , Baty Catherine J , Weisz Ora A 
Published: June 2021

The polarized epithelial cells that comprise the proximal tubule (PT) have a specialized apical endocytic pathway that allows for high‐capacity endocytosis which is necessary to recover essential nutrients and to maintain a protein‐free urine. Megalin, a multi‐ligand receptor at the apical surface of the epithelial cells, binds proteins in the ultrafiltrate and internalizes them via receptor‐mediated endocytosis. Ligands are sorted from receptors in endocytic compartments, and the receptors are recycled back to the surface. The molecular identities of the compartments involved in sorting and recycling in PT cells and the kinetics of megalin trafficking through them are unknown. When endocytosis in the proximal tubule is dysfunctional, tubular proteinuria results. Dent disease, an X‐linked disorder characterized by tubular proteinuria that progresses to renal failure, is caused by mutations in the Cl‐/H+ exchanger CLC‐5. Loss of CLC‐5 has been shown to reduce endocytic uptake and to decrease megalin protein expression without altering mRNA levels. However, the mechanism by which this occurs is unclear. We previously discovered that OK cells cultured under continuous fluid shear stress develop morphological and functional features similar to that of the PT in vivo, including high apical endocytic capacity and increased megalin expression. We used data obtained through biochemical approaches to estimate endocytic and recycling rates and the half‐life of surface megalin in untreated and CLC‐5 knockdown OK cells. These rates were used to construct a simplified model of megalin trafficking in differentiated PT cells. We present an ordinary differential equation (ODE) model of megalin trafficking describing surface and internalized pools of megalin with estimated kinetic parameters. We observed a greater fraction of internalized megalin compared to the surface pool due to an endocytic rate that is much faster than the recycling rate. We have quantified decreases in megalin expression and surface half‐life with loss of CLC‐5 expression. Current and future work includes quantifying alterations in megalin trafficking in CRISPR/Cas9 mediated CLC‐5 KO models and defining the structure and markers of the apical endocytic pathway by quantitative imaging to expand our model to include additional trafficking steps. This model will then be used to predict which steps in megalin trafficking are altered in Dent disease.Support or Funding InformationASN Pre‐Doctoral Fellowship, NIH R01‐DK101484, NIH P30‐DK079307This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Role of Beta‐2 Adrenergic Receptors in Cardiac Bioenergetics Following Severe Burns
Authors: El Ayadi Amina , Prasai Anesh , Jay Jayson , Bhattari Nisha , Guilory Ashley , Herndon David , Porter Craig , Finnerty Celeste 
Published: June 2021

Severe burn injury is characterized by increased energy expenditure, and altered mitochondrial function is thought to be central to the hypermetabolic response to burns. As catecholamines are an important driver of the hypermetabolic stress response to burn, we set out to determine the role of adrenergic signaling through Beta‐2 adrenergic receptors in cardiac mitochondrial function following burn. We hypothesized that a loss of adrenergic signaling would attenuate cardiac mitochondrial dysfunction in response to burns.We used beta ‐2 adrenergic receptor knockout mice (ADRB2‐KO) and wild type controls (WT). Mice received a 30% of total body surface area scald burn or a sham burn and were sacrificed one week following injury. Hearts were excised and mitochondrial function was measured in saponin‐permeabilized myofiber bundles by high‐resolution respirometry. Data were analyzed using two‐way ANOVA and Bonferroni post‐test to compare all groups.Mitochondrial respiratory capacity was significantly reduced in both WT (P<0.01) and KO (P<0.01) mice following burn, although there was no difference between WT and KO mice. In WT animals, respiration coupled to ATP production was significantly lower in the burn animals compared to shams (p< 0.05). In contrast, respiration coupled to ATP production was not different in sham and burn treated ADRB2‐KO mice. Mitochondrial flux control ratios (leak and couple respiration normalized to maximal uncoupled respiration) were significantly higher in burned WT mice compared to sham (P<0.05). However, mitochondrial flux control was not significantly altered by burn in KO mice.Collectively, these data underscore the role of catecholamines and adrenergic stress in the metabolic response to burns. Specifically, ablation of beta 2 adrenergic signaling in the heart prevents cardiac mitochondrial dysfunction in response to severe burn trauma.Support or Funding InformationThis study was supported by grants from the National Institute of Health (P50‐GM60338, R01‐GM56687, and GM 112936‐01), Shriners Hospitals for Children (80100, 87300, 71008, 70900, 85116, 71000), and SSF grant for Craig Porter. This study was also conducted with the support of the Institute for Translational Sciences at the University of Texas Medical Branch, supported in part by a Clinical and Translational Science Award (UL1TR000071) from the National Center for Advanc‐ing Translational Sciences, National Institutes of Health.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Contrasting Akt and p38 MAPK phosphorylation profiles in renal proximal tubular cells (RPTCs) exposed to lithium chloride and effects of lithium chloride on RPTC viability
Authors: Johnson Paul Richard , Rajayadhyaksha Medha , Wu Rui , Su Ruifen , Rane Madhavi J. 
Published: June 2021

Despite the success of lithium (Li) in the treatment of bipolar disorder, its effects on renal proximal tubular cell (RPTC) survival/death are unclear. Thus, the current study was initiated to determine effects of Li treatment on RPTC viability. RPTCs were treated with or without 10mM lithium chloride at several time points and cell lysates were immunoblotted with various antisera. Li induced Akt phosphorylation at 2 hr, which was down regulated by 24 hr. In contrast, Li induced p38 MAPK phosphorylation as early as 2 hr and was maximally phosphorylated at 24 hr and 48 hr. Akt inhibition failed to block Li‐induced p38 MAPK phosphorylation, suggesting that Akt activation occurs downstream of p38 MAPK. These studies were further confirmed by demonstrating that pharmacological blockade of p38 MAPK inhibited Li‐induced Akt and Hsp27 phosphorylation at 2 hr. However, Hsp27 phosphorylation was independent of Akt activation as demonstrated by Akt inhibition studies. In addition, Akt and p38 MAPK inhibition failed to block Li‐induced GSK‐3β phosphorylation, suggesting an Akt and p38 MAPK independent GSK‐3β inactivation in RPTCs. Furthermore, MTT assay demonstrated Li‐induced RPTC viability at 24 hr and 48 hr. The contributions of p38 MAPK in stimulating Li‐induced RPTC survival is currently under investigation.This work supported by NIAID [1R56AI059165‐01A2 (MJR)] AHA Scientist Development Grant [G03070 (MJR)]
Growth inhibition of human cholangiocarcinoma by sorafenib‐based mono‐ and combination treatment
Authors: Höpfner Michael , Baradari Viola , Huether Alexander , Scherübl Hans 
Published: June 2021

Background: Treatment options of advanced cholangiocarcinoma (CC) are unsatisfactory and new therapeutic approaches are mandatory. The Ras/Raf/MAPK‐pathway is one of the most significant cellular signaling sequences in the development and maintenance of cancer. Thus inhibition of this key signaling pathway appears to be a promising approach for novel CC‐treatment. Here we investigated the antineoplastic effects of sorafenib (Sor), a novel multi‐kinase inhibitor which potently suppresses wild‐type‐ and mutated Raf‐isoforms. Sor has already shown antineoplastic efficacy in some cancer types but its suitability for treatment of CC has not been investigated so far.Results: Sor dose‐dependently blocked growth‐factor‐induced MAPK‐activity and inhibited the proliferation CC cells in a time and dose‐dependent manner. At least two mechanisms accounted for the effects observed: G1/G0‐ arrest of the cell cycle and apoptosis. G1/G0‐arrest was associated with upregulation of the cdk‐inhibitor p27 and downregulation of cyclin D1. Combining Sor with doxorubicin, the HDAC inhibitor MS‐275 or IGF‐1R‐inhibition resulted in (over‐) addititve antiproliferative effects. Conclusion: Our study demonstrates that the growth of human CC cells can be potently suppressed by Sor alone or in certain combination therapies and may provide a promising rationale for future in vivo evaluations and clinical trials.
Augmented vasopressin secretion during low sodium diet: Sensitization by volume signals?
Authors: Bie Peter , Molstrom Simon 
Published: June 2021

Regulation of vasopressin secretion was studied in conscious dogs and in healthy volunteers. Dogs were fed regular diet or low‐salt diet (0.03 mmol kg−1 d−1) for 7 d. NaCl was infused i.v. at 0.02 mmol kg−1 min−1 in negligible volume for 3 h. Vasopressin V2 receptors were blocked by OPC 31260. Body fluid volume was maintained by servo‐controlled fluid infusion. On regular diet NaCl infusion elevated plasma Na+ and osmolality (pOsm) by 4.5% and elicited a 3‐fold increase in plasma vasopressin (pAVP, 1.58 ±0.24 to 4.39 ±0.40 pg ml−1). At low‐salt diet pAVP increased (1.74 ±0.13 to 4.94 ±0.68 pg ml−1) as a function of pOsm with similar slope (0.31 pg ml−1 (mOsm/kg)−1) but offset to the left by 6.2 mOsm/kg. Similar results were seen during β1‐receptor blockade (metoprolol, 2 mg/kg plus 0.9 mg h−1 kg−1). Human volunteers were studied after 4 d of low‐salt diet. Saline (135 mM) was infused i.v. providing 0.012 mmol Na+ min−1 kg−1 for 4 h (some 1500 ml). Arterial blood pressure (BP) did not change; heart rate (HR) fell by 5.8 ± 1.5 bpm (p<0.01); central venous pressure (CVP) increased by 1.7 ± 0.5 mmHg (p<0.025) concomitant with a fall in pAVP (3.0±0.4 to 1.8±0.1 pg ml−1, p<0.01). Identical results were obtained after metoprolol (0.3 mg/kg plus 0.06 mg h−1 kg−1) except that HR remained constant. The data are compatible with CVP mediated control of pAVP during low‐salt diet.Supported by the Danish MRC and the Novo Nordisk Foundation.
Essential amino acid supplementation maintains muscle function during bed rest in the elderly
Authors: Ferrando Arny A , Paddon‐Jones Doug , Kortebein Patrick , Ronsen Ola , Lombeida Juan , Symons T. Brock , Wolfe Robert R. , Evans William 
Published: June 2021

Older individuals are more likely to experience extended hospitalization. Thus, there is an inherent risk of prolonged inactivity and the accompanying functional decline. We have previously demonstrated that the provision of an essential amino acid (EAA) supplement in younger individuals subjected to 28d of bed rest eliminates the loss of lean body mass (LBM) and ameliorates the loss in muscle function. We hypothesized that EAA administration in older individuals subjected to 10d bed rest would also spare LBM and muscle function. Twenty‐two older subjects were given a placebo (n = 12, 68 ± 5 (SD) yrs, 83 ± 19 kg) or 15g of EAA (n = 10, 71 ± 6, 72 ± 8 kg) 3 times per day throughout 10d of bed rest. Measures of LBM, muscle protein synthesis, and muscle strength and function were determined before and after bed rest. Outcomes were tested statistically by 2X2 ANOVA and Tukey's post‐hoc test. EAA supplementation maintained muscle protein synthetic rate (P=0.025), but did not ameliorate the loss of LBM. EAA supplementation resulted in a preservation of plantar flexion strength (p=0.054), stair ascent power (p=0.029), stair descent power (p=0.026), and floor transfer time (p=0.027). Despite the inability of EAA to preserve LBM, muscle function was maintained. EAA supplementation maintains muscle protein turnover and preserves muscle function in older, inactive individuals.Project funded by the National Institutes of Health grant PO1 AG023591 (Evans).
Voluntary exercise modifies gene expression profiles in the nucleus tractus solitarii (NTS) of hypertensive rats
Authors: Potts Jeffrey T , Fong Angelina Y , Mueller Patrick J , McGovern David 
Published: June 2021

Regular exercise has beneficial effects on cardiovascular (CV) function. However, its affect on genetic components of brainstem nuceli is poorly understood. Since the NTS is essential for CV regulation, it may be a neural substrate for exercise‐induced CV adaptation. Rats (spontaneously hypertensive, SHR, n=4; Wistar‐Kyoto, WKY, n=4) performed voluntary wheel exercise (EX) for 12 weeks to screen for differentially expressed genes. Additional rats (n=4 per group) served as sedentary (SED) controls. Brainstems were harvested and NTS tissue was obtained by laser capture microscopy. Total RNA was hybridized to cDNA probes (Ratref12, Illumina) containing ~22,000 transcripts. The criterion for differential expression was > 2X difference in signal intensity. There was no significant difference in total distance (722±145 vs 594±91 km) or distance run per day (9±4 vs 7±3 km), SHR vs WKY. In SHR, exercise decreased resting blood pressure (131±3 vs 122±5 mmHg, P<0.05) and heart rate (311±14 vs 288±3 bpm, P<0.05), SHR‐SED vs SHR‐EX. No differences were found in WKY. Nineteen genes were differentially expressed in SHR‐EX (12 genes increased, 7 genes decreased). Of particular interest were genes involved in the inflammatory process (table).These results form the basis for future studies to elucidate mechanisms and links between voluntary exercise, NTS signaling and CV disease.
The stimulation of GIP secretion by lipid absorption – is it dose‐dependent?
Authors: Yoder Stephanie , Kindel Tammy , Li Hui , Xu Maggie , Tso Patrick 
Published: June 2021

The incretin hormone glucose‐dependent insulinotropic polypeptide (GIP) enhances glucose‐mediated insulin secretion. Following nutrient ingestion, GIP secretion by enteroendocrine K cells increases rapidly. Previous studies have shown that fat ingestion stimulates GIP release; however, it is unknown if there is a dose‐dependent secretion of incretins to the ingestion of fat. We hypothesize that a direct dose‐dependent relationship exists between the amount of lipid infused and GIP secretion. To test this, lymph fistula rats were used. Under halothane anesthesia, the major mesenteric lymph duct was cannulated, and an infusion tube was placed in the duodenum. Each animal received a single bolus intraduodenally of saline or varying amounts of the fat emulsion Liposyn II. Lymph was continuously collected for 6 hours and analyzed for GIP content. At lipid doses of 27.5 and 55 mg, the secretion of GIP, over the 6 hour period, increased 1 fold above the saline control; at lipid doses of 110, 220, and 440 mg lipid, GIP secretion increased 2 fold above the control. Thus, our data suggest that GIP secretion increases incrementally rather than dose‐dependently in response to a larger lipid dose. Whether this paradigm will be altered in diet induced obese animals is a question of considerable interest to basic and clinical scientists.Funded by DK076928‐01A(NIH/NIDDK)
STIM1 regulates store operated calcium entry (SOCE) in human airway smooth muscle
Authors: Thompson Michael A , Zhang David , Sieck Gary , Pabelick Christina , Prakash Y S 
Published: June 2021

Intracellular Ca2+ regulation in human airway smooth muscle (hASM) involves plasma membrane (PM) Ca2+ influx, including that triggered by sarcoplasmic reticulum (SR) Ca2+ depletion, i.e. store‐operated Ca2+ entry (SOCE). While transient receptor potential channels (e.g. TRPC3, TRPC4) are thought to mediate SOCE, the mechanisms triggering or regulating SOCE are being actively investigated. Recent studies suggest that stromal interaction molecule 1 (STIM1) acts as a signaling mediator between PM and SR, potentially regulating Ca2+entry via SOCE. In hASM, fluorescence microscopy and western blot analyses were used to verify the presence of STIM1. SR Ca2+ depletion with 10μM cyclopiazonic acid (CPA) resulted in increased STIM1 expression in the PM fraction, compared to controls. Transfection with 50nM STIM1 siRNA for 48h significantly decreased STIM1 levels. In cells where [Ca2+]i was measured using fura 2‐AM, SOCE was significantly reduced in cells transfected with STIM1 siRNA. Green‐fluorescent protein (GFP)‐tagged STIM1 transfection showed intracellular localization in non‐stimulated cells, with increased PM staining following CPA exposure. Subsequent immunostaining revealed co‐localization of STIM1 with TRPC3 and TRPC4. These results indicate that STIM1 is present in hASM and suggest a role for this protein in regulating SOCE.This work has been supported by NIH grants UL1RR024150‐01(CR to CMP, CR20 and Early Career Development Award to YSP), HL74309 (GCS), and the Department of Anesthesiology (CMP, YSP), Mayo Clinic College of Medicine, Rochester, MN
Repeated exposures to hyperbaric air suppress neurite outgrowth in PC12 cells
Authors: Isada Tetsuro , Hirose Munetaka , Murata Eri , Shigemi Kenji 
Published: June 2021

Objective: Scuba divers are at risk of central nervous system damage under hyperbaric exposure, which would directly causes lesions of neural cells.Method: After NGF stimulation, PC12 cells were compressed for 30 minutes as single exposure, and repeated exposures for 30 minutes were applied 3 times with intervals 3,15,30 minutes. Then neurite outgrowth was observed. Downstream signals of NGF (TrkA and ERK) were also examined under single and repeated exposures.Result: Repeated exposures to hyperbaric air with either 3 or 15 min interval suppresses NGF‐stimulated neurite outgrowth. Although TrkA showed no change in autophosphorylation, repeated exposures with 3 min interval reduced ERK protein expression significantly.Conclusion: Direct effect of repeated exposures to hyperbaric air on neural cells likely causes CNS lesions in scuba divers.
Effects of metformin on endothelial glycocalyx properties in db/db mice
Authors: VanTeeffelen Jurgen Willem , Eskens Bart , Zuurbier Coert , Vink Hans 
Published: June 2021

Recent studies show impaired glycocalyx properties during hyperglycemic conditions (1,2). The current aim was to determine the effects of the popular anti–diabetic drug metformin on glycocalyx properties. Db/db mice, 6–8 wks of age, were treated with metformin in their drinking‐water for 2 wks (MET, n=5); non‐treated db/db mice served as control (CON, n=5). At the experimental day, mice were infused with FITC–labeled 70 kDa dextrans (D70) and Texas Red‐labeled 40 kDa dextrans (D40), blood samples collected for 30 min, and plasma dextran concentrations determined using a spectrophotometer (2). Systemic glycocalyx D70 excluding volume was determined from the difference in initial distribution volume of D40 versus D70 (2,3), and was 0.009 ± 0.030 ml in CON and increased to 0.183 ± 0.057 ml in MET (p<0.05). The ratio of D70 to D40 clearance, reflecting glycocalyx barrier properties (2,3), was 0.619 ± 0.026 in CON and decreased to 0.530 ± 0.026 in MET (p<0.05). Dry to wet weight ratio, measured in heart and kidney, was 0.286 ±0.006 in CON and decreased to 0.257±0.009 in MET (p<0.05). Fasting blood glucose level was not changed in MET. These data show that MET treatment in db/db mice results in improved glycocalyx properties, irrespective of a change in fasting glucose. The glycocalyx improvement might underlie the observed restoration of organ fluid balance by metformin.Supported by Established Investigatorship from Netherlands Heart Foundation (2005T037) and Dutch Diabetes Research Foundation (2006.00.027)
Irreversible damage to rostral pontine nuclei (RPN) in adult awake goats attenuates a secondary physiologic response to hypoxia
Authors: Bonis Joshua M , Davis Suzanne , Kiner Tom , Krause Katie , Qian Baogang , Pan Lawrence , Forster Hubert 
Published: June 2021

We chronically implanted microtubules into the rostral pons of 6 goats to assess the response to hypoxia following irreversible damage to RPN. All goats recovered uneventfully after implantation. After breathing room air for 30 minutes (min), goats were subjected to 10.6% O2 for 30 min. PaO2 at min 6 and 26 of hypoxia was 28.41±0.57 and 26.87±0.58mmHg respectively. The normal response to hypoxia (Table) was a 1° (∼3 min) spike in pulmonary ventilation (VI) followed by a “roll‐off” in VI (∼6 min), and lastly a 2° increase in VI (within 20 min) associated with an increase in body temperature, shivering, VO2, and VCO2. Following irreversible damage to RPN, the 1° spike and “roll‐off” in VI were unchanged from pre‐damage conditions, but the 2° increase was attenuated (P<0.05). We conclude that damage to RPN does not alter the presumed peripheral chemoreceptor 1° response to hypoxia nor the VI “roll‐off”, but attenuates the 2° physiologic response.
Comparison of physiologic variables in response to hypoxia, before and after RPN damage.

VE(%)
PaCO2(Δ mmHg)
Temp(Δ °C)
VO2 (l/min)
VCO2 (l/min)

1° increase
Roll‐off
2° increase
6 min hypoxia
26 min hypoxia
Final
26 min hypoxia
26 min hypoxia

Pre‐damage
174
130
251
−5.47
−8.18
0.96
158.1
197.1

Post‐damage
176
128
195*
−5.31
−6.82
0.59*
8.9*
85.1*

Significant difference between pre‐ and post‐damage by one‐way ANOVA (P<0.05). Supported s.