bluuebunny/crossref_metadata_2025_split huggingface dataset:
Centrally administered Ang‐(1‐7) via Mas receptors reverses psychosocial stress‐induced cardiovascular responses in mice with muscular dystrophy
Authors: Yang Liping , Pang Hong Weng , Speth Robert C. , Narayanan Nandakumar , Weiss Robert M. , Sabharwal Rasna 
Published: June 2021

Muscular dystrophy is a devastating disease of muscle weakness, atrophy and dilated cardiomyopathy (DCM). We have demonstrated that angiotensin II (Ang II)‐dependent autonomic dysfunction precedes and predicts development of DCM in sarcoglycan delta deficient (Sgcd−/−) mice, an established model of muscular dystrophy [Exp Physiol 2015]. More recently, we found that Sgcd−/− mice exhibit depression‐like behaviors and are susceptible to psychosocial stress‐induced bradycardia, hypotension and arrhythmias at older ages (>45 weeks of age) [FASEB J 2017]. Thus, we hypothesized that central administration of angiotensin‐(1‐7) in older Sgcd−/− mice protects against Ang II‐mediated cardiovascular abnormalities during acute psychosocial stress challenge. Mean blood pressure (MAP) and heart rate (HR) were measured by telemetry in control C57BL6 (n=3–5) and Sgcd−/− (n=3–8) mice during social defeat (~15 min exposure to intruder mouse). At 40±3 weeks of age, mice were randomly assigned to one of the four experimental groups – (i) vehicle (saline); (ii) losartan (Ang II‐type 1 receptor antagonist, 1 mcg/kg/hr); (iii) Ang‐(1‐7) (100 ng/kg/hr); and (iv) Ang‐(1‐7)+Mas antagonist A779 (100 ng/kg/hr and 0.5 mcg/kg/hr, respectively). Drugs were administered ICV (catheter connected to osmotic minipump) for 8 weeks. Stressed Sgcd−/− mice exhibit an increase in AT1R‐binding (receptor autoradiography) in subfornical organ, organum vasculosum laminae terminalis, and paraventricular nucleus of hypothalamus. Social defeat produced profound bradycardia and hypotension in Sgcd−/− mice (see Table). Interestingly, while these drastic effects on MAP and HR in Sgcd−/− mice were modestly attenuated by losartan, the effects were completely abolished by Ang‐(1‐7) (P<0.05 vs. vehicle) and remained unaltered by Ang‐(1‐7)+A779 (NS vs. vehicle). Moreover, the increased plasma corticosterone (+86%) and norepinephrine (+62%) in stressed Sgcd−/− mice were normalized by Ang‐(1‐7) (P<0.05 vs. control).We conclude that Ang‐(1‐7) acting centrally via Mas receptors abrogates cardiovascular response to psychosocial stress and is likely a more effective treatment strategy than Ang II‐type 1 receptor antagonists in muscular dystrophy.Support or Funding InformationAHA GIA17GRNT33670004This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The role of microRNA‐195 in age‐dependent impairment of cognitive function
Authors: Chan Julie YH. , Chao Yung‐Mei , Juo Suh‐Hang 
Published: June 2021

MicroRNA‐195 (miR‐195) is a member of the miR‐16/15/195/424/497 family. It is abundantly expressed in normal tissue, including the brain. Recently, an anti‐senescence role of miR‐195 was reported. However, its significance in age‐associated change in cognitive function has not been properly characterized. Using a tamoxifen‐inducible miR‐195 knock out (miR‐195+/− KO) mice based on the Cre‐loxP system, we compared in this study temporal profiling of cognitive functions in the mice at age of 3, 6, 9, 12 and 15 months to their wild type (WT) control. The Morris water maze was performed to evaluate cognitive function, sequential magnetic resonance imaging (MRI), coupled with diffusion tensor imaging (DTI) acquisition was carried out to evaluate the brain connectivity. In both WT and miR‐195+/− KO mice, the slope of time latency to reach the hidden platform in the water maze during the 5 consecutive training days became gentle, but not different between the two groups, suggesting there is no difference in the age dependency of learning in both groups. However, at 12 and 15 months of age, both preference and time spending in the target quadrant were notably shorter in miR‐195+/− KO mice, compared to the WT mice. There is no difference in total distance traveled and velocity between WT and miR‐195+/− KO mice during the tests, suggesting the locomotor ability was not affected in the KO mice. Next generation sequence analysis further revealed that among the target genes of miR‐195, expression of both Plexin‐A1 and its ligand, Sema3A, were significantly increased in the hippocampus of miR‐195+/− KO mice. Sema3A binds with Plexin‐A1 to induce neuronal apoptosis. Tractographic analysis based on MRI/DTI of forebrain image revealed no apparent change in connectivity between the hippocampus and cortical areas of both WT and miR‐195+/− KO mice at age of 12 or 15 months. Taken together, these data indicate that while miR‐195 may not play a permissive role in spatial learning, it is crucial for memory retrieving during aging process. This may mediate via suppression of neuronal apoptosis in the hippocampus when changes in hippocampal‐cortical neural connectivity are not yet bechanced.Support or Funding InformationMOST106‐2314‐B182A‐003 from the Ministry of Science and Technology, Taiwan; OMRPG8G0011 from Chang Gung Medical Foundation, TaiwanThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Influences of Ethanol on Inflammation and Apoptosis Following Transient Focal Cerebral Ischemia
Authors: Li Chun , Xu Guodong , Parsiola Anne L. , Li Jiyu , McCarter Kimberly D. , Sun Hong 
Published: June 2021

BackgroundInflammation and apoptosis are two key elements involved in cerebral ischemia/reperfusion (I/R) injury. Ethanol is one of the most commonly and regularly used chemical substances. We determined the influences of chronic ethanol consumption on inflammation and apoptosis following transient focal cerebral ischemia.MethodsMale C57/BL6J mice were divided into 6 groups and gavage fed with 0.175, 0.35, 0.7, 1.4, 2.8 g/kg/d ethanol or volume‐matched water once a day for eight weeks. Cerebral I/R injury, adhesion molecules, microglial activation, neutrophil infiltration, pro‐ and anti‐inflammatory cytokines/chemokines, MMPs, cleaved caspase‐3‐positive neurons, and TUNEL‐positive neurons were evaluated at 24 hours after a 90‐minute unilateral middle cerebral artery occlusion (MCAO).ResultsCerebral I/R injury was only significantly reduced in 0.7 g/kg/d ethanol group (peak blood ethanol concentration: 9 mM) and increased in 2.8 g/kg/d ethanol group (peak blood ethanol concentration: 37 mM). Baseline and post‐ischemic upregulation of ICAM‐1 and E‐selectin were suppressed in all ethanol groups. Post‐ischemic microglial activation and neutrophil infiltration were significantly alleviated in 0.175–1.4 g/kg/d ethanol groups but dramatically exacerbated in 2.8 g/kg/d ethanol group. Ethanol tends to dose‐dependently increase both baseline pro‐ and anti‐inflammatory cytokines/chemokines, but dose‐dependently suppressed post‐ischemic increase in pro‐inflammatory cytokines/chemokines. Surprisingly, 2.8 g/kg/d ethanol strengthened post‐ischemic increase in anti‐inflammatory cytokines/chemokines. Furthermore, although baseline MMP‐9 activity was reduced in 0.7 g/kg/d ethanol group, the magnitude of post‐ischemic increase in MMP‐9 activity was significantly less in 2.8 g/kg/d ethanol group. Both cleaved caspase‐3‐positive neurons and TUNEL‐positive neurons were significantly less in 0.7 g/kg/d ethanol group.ConclusionsLight alcohol consumption protects against cerebral I/R injury by suppressing post‐ischemic inflammation and apoptosis, whereas heavy alcohol consumption may exacerbate cerebral I/R injury via an inflammation‐ and apoptosis‐independent mechanism.Support or Funding InformationThis study was supported by a National Institutes of Health Grant (AA023610) and funds from Louisiana State University Health Sciences Center‐Shreveport to HS, a postdoctoral fellowship to CL and a predoctoral fellowship to KDM from the Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Science Center‐Shreveport.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
C1q Intrathecal synthesis in patients without inflammatory diseases with blood‐brain dysfunction
Authors: Lumpuy‐Castillo Jairo , González‐Losada Cristobal , Schmitz Matthias , Hansen Anette Gudmann , Jensenius Jens Christian , Dorta‐Contreras Alberto Juan 
Published: June 2021

The role of complement system in the central nervous system is not enough clarified. For this reason it requires to know what happen in extreme situations. The objective is to know if under blood‐cerebrospinal fluid dysfunction how the classical complement pathway by analyzing C1q is possible to be intrathecally synthesized. It should consider three topics: the molecular size dependent concentration between CSF and blood. The transfer variation between blood and CSF and, and the CSF C1q concentration correlation with the albumin CSF/serum quotient (QAlb). C1q was assayed in samples of CSF and serum by ELISA. Albumin, immunoglobulin‐CSF/serum quotients, oligoclonal IgG and cell count were used to characterize the control groups. Group comprised 20 patients without inflammatory diseases but with increased QAlb. C1q concentration in CSF was at least five‐fold higher than expected for a molecular‐size‐dependent passage from blood. In a QC1q/QAlb quotient diagram 7/20 cases showed an intrathecal fraction in some cases over 80% of total CSF C1q concentration. The absolute C1q concentration in CSF increases with increasing Q Alb. C1q is possible to be intrathecally synthetized in patients with blood brain barrier dysfunctionThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
M Ficolin: Diffusion dynamics from Blood to Cerebrospinal Fluid
Authors: Castillo‐González William , González‐Losada Cristobal , Lumpuy‐Castillo Jairo , Rodriguez‐Pérez Jose Alejandro , Jensenius Jens Christian , Zerr Inga , Schmitz Matthias , Dorta‐Contreras Alberto Juan 
Published: June 2021

INTRODUCTIONFicolins belong to the lectins family. They activate the complement system as an effect in defence of the carrier, and play a very important role in the innate immunity.Three kinds of human Ficolins were earlier described: L, H and M ones. The theory of molecular dissemination is the basis of the behavior's approach from these proteins that can be found in cerebrospinal fluid (CSF).OBJECTIVETo demonstrate through the dynamic of the dissemination from blood to CSF and its concentrations the different ways of molecular adding towards CSF and its action in this biological liquid.METHODS80 serum and CSF paired samples were obtained from control persons without neuroinflammation process and without oligoclonal IgG bands. M ficolin and albumin were quantified by ELISA and by an immunoturbidimetric analysis. Q albumin=CSF albumin/serum albumin and Q, M Ficolin=CSF M Ficolin/serum M ficolin was calculated.To calculate the different aggregation forms were determinate the inflection points of the frequency distribution of M ficolin vs. Q M Ficolin taking into account that the more complex structure should diffuse more than a most simple one.RESULTSSerum and CSF M ficolin did not follow a normal distribution according to Kolmogorov‐Smirnov test. Mean values of M ficolin in serum was higher than its mean content in CSF. CSF M ficolin concentration increased with the increase of Q albumin. M ficolin is not a brain‐derived protein. Three inflection points was determined. (Table 1 and figure 1). G‐1, G‐2, G‐3 described the subpopulation of samples diffusion limited by their molecular weight and its aggregation structure.CONCLUSIONM ficolin is a predominant blood‐derived protein and the diffusion from blood to CSF indicates three aggregation forms.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 Arginine Vasopressin (AVP) Deficiency, Conivaptan and Desmopressin on Clinical Symptoms and Blood Cytokine Levels in Rats with Experimental Autoimmune Encephalomyelitis
Authors: Quintanar‐Stephano Andres , Viñuela‐Berni Veronica , Macías‐Segura Noé , Valdez‐Urias Fernando , Kovacs Kalman Thomas 
Published: June 2021

IntroductionThe experimental autoimmune encephalomyelitis (EAE), the rat paradigm for the human multiple sclerosis (MS), are autoimmune diseases mediated by Th1 and Th17 cells and responsible of the nervous system demyelination and progressive paralysis. It is know that lymphocytes possess AVP receptors and that EAE increases AVP serum levels along the disease. Neurointermediate pituitary lobectomy (NIL) in rats causes AVP and oxytocin permanent low serum levels and decreased humoral and cell‐mediated immune responses. Nevertheless the role of AVP as a direct immune regulatory factor has not been well clarified.ObjectiveTo investigate the effects of AVP deficiency (by NIL), and the treatment with desmopressin (DP, a synthetic analog of AVP) and conivaptan (CNV, an AVP V1a‐V2 receptor antagonist) on the clinical symptoms of EAE, and to determine the serum levels of Interleukine‐2 (IL‐2), IL‐4, IL‐6, IL‐10, IL‐17A, INF‐γ and TNF‐α in the experimental groups.MethodsGroups of female Lewis rats were divided in: (1) Intact control (Control) (2) Control+EAE, (3) Sham‐operated (SHAM), (4) Control+CNV, (5) NIL and (6) NIL+DP. Except the Control the remaining groups were immunized for EAE three weeks post‐NIL. DP and CNV administrations started 3 days before EAE immunizations. Serum cytokines were analyzed by flow cytometry and EAE clinical symptoms were evaluated by a conventional numerical scale.ResultsEAE clinical symptoms, INF‐γ, TNF‐α, and the IL‐2, IL‐6 and IL‐17A were significantly decreased in both NIL and CNV groups, whereas the IL‐4 and IL‐10 increased in the CNV group. In NIL+DP group we found a significant increase in TNF‐α, whereas the IL‐4 was significantly decreased.Conclusions1) The present clinical and molecular findings demonstrate that AVP deficiency and the block of the AVP receptors decreased immune response, and that DP restores the susceptibility of the NIL animals to develop EAE. 2) The results strongly support that acting directly on the AVP receptors, AVP plays an important immuneregulatory role in the generation and maintenance of the immune‐competence, 3) AVP receptors may be therapeutic targets in the treatment of the human MS.Support or Funding InformationSupported by UAA‐PIFF14‐1 and CONACYT‐221262 (AQS). México.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Basolateral FFA2 of enterochromaffin cells contributes to 5‐HT release in rat and mouse duodenum
Authors: Akiba Yasutada , Takajo Takeshi , Kaunitz Jonathan D. 
Published: June 2021

Enteroendocrine cells (EEC) express nutrient receptors that when activated release hormones such as serotonin (5‐HT). Although nutrient receptors are thought to be localized on the apical membrane of EEC, where they are well placed to sense luminal nutrients, immunohistochemistry mostly localizes the receptors to the cytosol or to either membrane pole. Since villous cells transport luminal nutrients via nutrient transporters or by passive diffusion to the submucosal space, it is possible that absorbed nutrients activate basolaterally‐expressed nutrient receptors rather than detect luminal nutrients. One of the short‐chain fatty acid receptors, FFA2, is expressed on enterochromaffin (EC) cells of rat duodenum; its activation increases HCO3− secretion in vivo, accompanied by 5‐HT release into the portal vein and mediated by 5‐HT4 receptor activation. We thus used muscle‐stripped mucosa‐submucosa preparations of rat and mouse duodenum mounted in Ussing chambers to pharmacologically localize FFA2 to the apical or basolateral membranes of EC cells.The selective and allosteric FFA2 agonist phenylacetamide‐1 (PA1) was applied to the mucosal or serosal bath of the Ussing chamber, where short‐circuit current (Isc) was measured in the presence of serosal indomethacin (10 μM).PA1 (1 – 100 μM) in the mucosal bath had no effect or slightly decreased Isc in both rat and mouse duodenum. In contrast, PA1 in the serosal bath dose‐dependently increased Isc that was greater in mouse than in rat duodenum; in both, the PA1‐induce Isc increase was reduced by the 5‐HT3 receptor antagonist granisetron (Gran, 10 μM) and abolished by the 5‐HT4 receptor antagonist GR113801 (GR; 10 μM). The effect of serosal PA1 was inhibited by the selective FFA2 antagonist GLPG0974 (0.1 mM). Furthermore, the native FFA2 agonists sodium acetate and sodium propionate (pH adjusted to pH 7.4) dose‐dependently increased Isc inhibited by GR, Gran, the selective Nav1.8 antagonist A803467, and the selective neurokinin receptor‐1 (NK‐1) antagonist CP99994, but not by TTX or atropine. Serosal PA1 increased serosal 5‐HT concentrations, which were not affected by TTX+A803467. FFA2 immunoreactivity was limited to EC cells, suggesting that EC cells rather than myenteric neurons are the primary source of 5‐HT.These results suggest that FFA2 is localized at least to the basolateral membrane of EC cells and that its activation increases electrogenic anion secretion. The basolateral location of FFA2 is important for informing the design of experimental and clinical studies aimed at altering 5‐HT release from EC cells, which is related to mucosal defenses and dyspeptic symptoms.Support or Funding InformationVA Merit Review and NIDDK R01 DK54221This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Intestinal epithelial‐specific NHE3 knockout causes metabolic acidosis
Authors: Valdez Alexandria , Dominguez Rieg Jessica A. , Fenton Robert A. , Rieg Timo 
Published: June 2021

The Na+/H+ exchanger isoform 3 (NHE3) has an important role in intestinal and renal Na+ uptake and acid‐base regulation. While renal‐specific NHE3 knockout models have been successfully generated, no intestinal‐specific model has been described. Of note, renal‐specific NHE3 knockout does not result in altered blood pH or bicarbonate levels (Kidney International; 2017, 92:397–414) and conventional intestinal epithelial cell‐specific NHE3 knockout mice die shortly after birth. To determine the role of NHE3 selectively in the intestine, we generated tamoxifen (Tam)‐inducible epithelial‐specific NHE3 knockout mice (NHE3IEC‐KO) by intercrossing NHE3loxlox (control, Con) and VillinCreERT2 mice. Semiquantitative fluorescent labeling determined that application of Tam (5 days, 200 mg/kg via oral gavage) deleted NHE3 from the small intestine and colon of NHE3IEC‐KO mice, whereas labeling in the proximal tubule and thick ascending limb of the kidney was unaffected. Before Tam, Con and NHE3IEC‐KO (n=8 and 4, respectively) mice had comparable blood pH (7.4±0.01 vs 7.4±0.01), HCO3− (24.7±0.7 vs 24.6±0.6 mM), base excess (0.5±0.2 vs 0.6±0.1 mM) and Na+ concentrations (147±0.4 vs 148±0.8 mM). Two weeks after Tam, compared to Con mice, NHE3IEC‐KO mice show significant metabolic acidosis (Δ change: 0±0.01 vs −0.15±0.03, P<0.05), lower HCO3− (Δ change: 0±0.4 vs −7±1, P<0.05) and negative base excess (Δ change: 0±0.7 vs −9±2, P<0.05), whereas plasma Na+ was unaffected (Δ change: 0.5±0.6 vs −0.3±1, NS). Indirect evidence for impaired intestinal HCO3− uptake using intestinal flushes showed a significantly higher flush pH in NHE3IEC‐KO compared to Con mice (7.9±0.1 vs 7.4±0.1, P<0.05). In conclusion, we successfully generated intestinal epithelial cell‐specific NHE3 knockout mice. The mouse model will be useful to study different aspects of NHE3 in the intestine and colon. The data indicate a prominent unrecognized role of the intestine for acid‐base regulation.Support or Funding InformationNovo Nordisk Foundation, the Lundbeck Foundation, Danish Medical Research Council, NIH 1R01DK110621, APS STRIDE Undergraduate Summer Research Fellowship 1R25HL115473‐01This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Concurrent Airway Surface Liquid Absorption and Secretion in Human Bronchioles
Authors: Shamsuddin A. K. M. , Quinton Paul M. 
Published: June 2021

Characterization of epithelial fluid and electrolyte transport in native small airway epithelia has been largely neglected due to the complex tissue architecture as well as by its inaccessibility and lack of applicable assays, especially in human tissues. To better understand how airway surface liquid (ASL) is maintained as a balance between absorbing and secreting functions, we measure ion transport properties of bronchioles with diameters of 1–2 mm isolated from freshly resected specimens of human lungs with a “mini”‐Ussing chamber (area≈1 mm2). We determined the effects of inhibiting absorption by applying amiloride to inhibit Na+ conductance through ENaC and secretion by applying bumetanide to inhibit the Na+‐K+‐2Cl− cotransporter to block Cldependent secretion demonstrated spontaneous absorptive as well as secretory short circuit currents in bilateral 150 mM NaCl‐Ringer solution. We also tested for the presence of the Clchannels, CFTR stimulating with Fsk/IBMX and CaCC with UTP. Both agonists independently stimulated additive equivalent short circuit current in the same specimen of small airway tissue, but evoked distinctly opposite effects on the transepithelial potential (Vt). While Fsk/IBMX (cAMP) activation depolarized Vt, UTP (Ca2+) stimulation hyperpolarized the Vt. The depolarization of Vt induced by cAMP suggests that activating CFTR may stimulate fluid absorption, while hyperpolarization of Vt by Ca2+ (UTP) suggest that activating CaCC may stimulate fluid secretion. Independent regulation of these fluid movements may be critical to regulation of ASL volume during conditions of stress. Human small airways constitutively and concurrently secrete and absorb fluid, structurally separated and independent epithelial cells for liquid secretion and absorption. Our results present new evidence for how the delicate layer of fluid lining the small airways is physiologically maintained in a steady state and appropriate airway hydration.Support or Funding InformationThe Nancy Olmsted Trust and the Cystic Fibrosis Research Inc. (CFRI).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.