bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spinal Instability in Rats Counteracted by Pentadecapeptide BPC 157
Authors: Dokuzovic Stjepan , Bebek Igor , Perovic Darko , Bilic Vide , Corluka Stipe , Krezic Ivan , Durasin Tajana , Drmic Domagoj , Seiwerth Sven , Sikiric Predrag 
Published: June 2021

To induce spinal instability, we focused on bilateral facetectomy in rats and possible therapeutic benefit with the stable gastric pentadecapeptide BPC 157 given in the drinking water. Recently, using a well‐designed rat model (L2‐L3 compression), we demonstrated that the stable gastric pentadecapeptide BPC 157 improved the spinal cord injury (FASEB J 2015, 29, 617.5), concluding that under the conditions of one single application, given soon after spinal cord injury, motor function was markedly recovered, axonal and neuronal necrosis was counteracted, as was demyelination and cyst formation. Previously shown to counteract the consequence of peripheral (sciatic) nerve transection/anastomosis, improve nerve healing (Regul Pept. 2010 Feb 25;160(1–3):33–41.), brain trauma (Regul Pept. 2010;160(1–3):26–32.), and various encephalopathies (Curr Pharm Des. 2018;24(18):1990–2001), BPC 157 (LD1 not achieved) was implemented as an anti‐ulcer peptide in inflammatory bowel disease trials and now in a multiple sclerosis trial(Curr Pharm Des. 2018;24(18):1990–2001). In this study, the bilateral paravertebral muscles attached to the L3–L4 segment were peeled from the lumbar spine to expose the posterior bony elements. The rats then underwent complete resection of bilateral L3–L4 facet joints without neural tissue injuries. The medication was given in drinking water (BPC 157 10 ng/kg, 0.16 ng/mL, 12 ml/rat/day) through next 8 weeks, while controls received drinking water only. Radiological assesment of rat spines acquired at 1 week or 8 weeks was conducted (Figure 1). At 1 week, controls and BPC 157 animals exhibited no gross deformity observed in any plane, disk spaces seem unaffected, neural foramen at operated level is slightly widened, though BPC 157 drinking animals had higher bone density overall. At 8 weeks, both groups exhibited no gross deformity observed in any plane, unaffected disk spaces, widened neural foramen at the operated level is slightly widened, though there was an additional discrepancy in bone density overall between groups (BPC 157 having markedly more sclerotic and better defined bones). Also worth noting is the lack of abundant callus formation in the BPC 157 rats whereas the controls have visible callus formation in seemingly random patterns near the affected level. In addition, a significant motor disability which appears in controls immediately upon injury induction, was completely counteracted in BPC 157 drinking rats.Support or Funding InformationThis work was supported by the Ministry of Science, Education and Sports, Republic of Croatia [grant number 108‐1083570‐3635].This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Stable Gastric Pentadecapeptide BPC 157 Recovers Motor Function After Rat Spinal Cord Injury
Authors: Perovic Darko , Krezic Ivan , Dokuzovic Stjepan , Bilic Vide , Gojkovic Slaven , Drmic Domagoj , Seiwerth Sven , Sikiric Predrag 
Published: June 2021

Using a well‐designed rat model, we demonstrated that the stable gastric pentadecapeptide BPC 157 improved the spinal cord injury (FASEB J 2015, 29, 617.5). Previously shown to counteract the consequence of peripheral (sciatic) nerve transection/anastomosis, and improve nerve healing (Regul Pept. 2010 Feb 25;160(1–3):33–41.), and brain trauma (Regul Pept. 2010 Feb 25;160(1–3):26–32.), and various encephalopathies (Curr Pharm Des. 2018;24(18):1990–2001), BPC 157, LD1 not achieved, was implemented as an anti‐ulcer peptide in inflammatory bowel disease trials and now in a multiple sclerosis trial(Curr Pharm Des. 2018;24(18):1990–2001). In a study from the day 1 to 1 year, rats underwent laminectomy (level L2–L3), 60 second compression (neurosurgical piston (60–66 g) on exposed dural sac with sacrocaudal spinal cord) received one medication of BPC 157 (200 or 2 μg/kg) or saline (5 ml/kg)) intraperitoneally at 10 min after injury (FASEB J 2015, 29, 617.5). All injured rats underwent BPC 157 exhibit consistent improvement, clinically, constantly better tail motor function, no autotomy; resolved spasticity already by the day 15; microscopically (since day 7), vacuolas and loss of axons in white matter, edema and loss of motoneurons in gray matter, and decrease of the number of large myelinated axons in rat caudal nerve were largely counteracted in BPC 157 rats. EMG recording evidences markedly lower MUP in tail muscle. Concluding, under the conditions of one single application, given soon after spinal cord injury, counteracted were axonal and neuronal necrosis, demyelination, cyst formation. Now, to create, however, a more reliable situation and therapy effect, the therapy with BPC 157 was started after 4 days. The medication was given in drinking water (BPC 157 10 μg/kg, 0.16 μg/mL, 12 ml/rat/day) through next 4 weeks, while controls received drinking water only. Specifically, tail motor function was scored as follows: 1 ‐ complete loss of tail function; 2 ‐ elevation maximum of 1/4 of tail length; 3 ‐ elevation maximum of 1/2 of tail; 4 ‐ elevation maximum of 3/4 of tail length; 5 – normal function. During evaluation, tail motor function score remained debilitated in rats underwent spinal cord injury that received post‐injury. Contrarily, BPC 157 treated rats exhibited huge improvement, which was continued to full recovery.ConclusionWe documented that even given later after injury, the neuroprotective effect of BPC 157 quickly appears, and, BPC 157 given in drinking water, accordingly recovers the failed motor function in rats with spinal cord injury.Support or Funding InformationThis work was supported by the Ministry of Science, Education and Sports, Republic of Croatia [grant number 108‐1083570‐3635] .This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ataxia in the ASIC5 Knockout Mouse Associated with Decreased Excitability of Vestibulocerebellum Unipolar Brush Cells
Authors: Boiko Nina Y. , Kreko‐Pierce Tabita , Pugh Jason , Stockand James D. 
Published: June 2021

Acid‐sensing ion channels (ASICs) are neuronal ligand‐gated sodium channels. They are the members of the Degenerin/Epithelial Na+ channel (Deg/ENaC) family. In mammalian neurons ASICs play an important role in a variety of complex behaviors such as fear, pain, anxiety, learning, and memory. Among all five members of ASIC1‐5 channels, ASIC5 is least known. To reveal the expression and function of this channel we generated ASIC5 reporter and knockout mice. We found that ASIC5 is restrictively expressed in a subset of interneurons in the granular layer of nodulus of the vestibulocerebellum. Immunohistochemical and morphological analysis identified these interneurons as unipolar brush cells (UBC) that also express the metabotropic glutamate receptor 1α (mGluR1α). Such observations are consistent with ASIC5 playing a key role in the physiology of UBCs and in the function of the vestibulocerebellum. Consistent with this, knockout of ASIC5 results in ataxia and uncoordinated bodily movements. Electrophysiological analysis of UBC revealed a decrease in excitability of these neurons in the ASIC5 knockout mice that underlies these behavioral dysfunctions.Support or Funding InformationThis work was funded by a NIH Ro1 grant (DK113816)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Functional properties of mouse ferroportin, a cellular iron‐export protein
Authors: Azucenas Corbin P , Bonamer John P , Ruwe T Alex , Qiao Bo , Ganz Tomas , Nemeth Elizabeta , Mackenzie Bryan 
Published: June 2021

Iron homeostasis is a topic of great public‐health importance because of the high prevalence of iron‐deficiency anemia and of hereditary disorders that cause iron overload. Ferroportin (Fpn)—the only known mammalian cellular iron exporter—is expressed on the plasma membrane of macrophages, enterocytes, and hepatocytes. Fpn, under the control of the iron‐regulatory hormone hepcidin, serves a critical role in the regulation of systemic iron. Whereas we have previously characterized the functional properties of human Fpn, a great deal of research in iron homeostasis utilizes mouse models, highlighting the need to study mouse Fpn in vitro. For example, the flatiron mouse model of classical ferroportin disease bears the mutation H32R in mFpn and is characterized by systemic iron deficiency and macrophage iron loading. The flatiron mouse also appears to exhibit a manganese phenotype [Seo YA and Wessling‐Resnick M (2015) FASEB J 28, 2726–2733], raising the possibility that mouse Fpn (mFpn) serves a role in Mn metabolism, although Mn is not a substrate of human Fpn. We therefore tested the hypothesis that mouse but not human Fpn can transport Mn. We characterized the functional properties of mFpn by using radiotracer assays in RNA‐injected Xenopus oocytes expressing mouse or human Fpn. We found that mFpn can export several transition metals, with selectivity Fe > Co > Ni, but not Cd. Whereas the H32R mutant abolished mFpn‐mediated Fe efflux relative to wildtype, neither wildtype nor mutant mFpn could transport Mn. mFpn‐mediated Fe efflux was pH‐dependent with estimated optimal pH of 8.2 ± (SEM) 0.2 when [Ca2+]o = 2 mM. mFpn‐mediated Fe efflux was activated by extracellular Ca2+, proceeded independently of extracellular Na+, and was inhibited 51% ± 1% by 10 μM hepcidin (30‐min preincubation). Our data (i) reveal that human and mouse Fpn share similar functional properties and (ii) do not support the notion that Fpn can transport Mn.Support or Funding InformationNIH grants R01 DK107309, P30 DK078392, and R25 HL115473, and the American Physiological SocietyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Identification of novel, potent and selective inhibitor of VRAC
Authors: Jeon Dong‐Kyu , Namkung Wan 
Published: June 2021

Tight regulation of cell volume is essential for normal cell function. Sudden changes in the osmolarity of the extracellular fluid (ECF) cause cell swelling or shrinkage, and leads to regulatory volume decrease (RVD) and regulatory volume increase (RVI). In the cell volume regulation, RVD involves activation of ion transport which mediates the efflux of K+ and Clfrom the cells. The volume‐regulated anion channel (VRAC) is involved in Cl− efflux and plays a pivotal role in the regulation of cell volume. In addition, it is known that various processes such as cell division, migration, necrotic and apoptotic cell death are directly related to VRAC. Short circuit current measurement in FRT cells expressing ANO1 chloride channel revealed that the most potent and selective VRAC inhibitor, DCPIB, strongly inhibited ANO1 chloride current. Several cell lines express both ANO1 and VRAC, and there is cross talk between these chloride channels. Thus, the lack of selective inhibitors of VRAC limits VRAC and ANO1 research. In this study, we performed a cell‐based high‐throughput screening to identify potent and selective VRAC inhibitors. Screening of 55,000 compounds and electrophysiological studies revealed a novel, potent and selective VRAC inhibitor, VRACi‐A01 (IC50 = 2.7 μM). It did not affect the ANO1 chloride channel activity at the concentration showing complete inhibition of VRAC. To the best of our knowledge, VRACi‐A01 is the most potent and selective VRAC inhibitor reported to date and a useful research tool for pharmacological dissection of VRAC in the cells expressing VRAC and ANO1.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
MicroRNA‐103a plays a role in regulating human sodium‐dependent vitamin C transporter‐1 (hSVCT1) in intestinal epithelial cells
Authors: SUBRAMANIAN VEEDAMALI , Sabui Subrata , Marchant Jonathan , Said Hamid 
Published: June 2021

Ascorbic acid (AA; vitamin C) is essential for normal human health and well‐being. Vitamin C acts as a cofactor for many important enzymatic reactions and is a potent antioxidant. Humans cannot synthesize vitamin C endogenously and obtain the vitamin from dietary sources via intestinal absorption, a process that involves the human sodium‐dependent vitamin C transporters‐1 &‐2 (hSVCT1 and hSVCT2; products of the SLC23A1 and SLC23A2 genes, respectively). Previous studies have shown that hSVCT1 is predominantly expressed in the intestine and localized at the apical membrane of polarized enterocytes where it mediates AA absorption. Thus, hSVCT1 expression levels are an important determinant of physiological vitamin C homeostasis. To date, little is known about post‐transcriptional mechanisms that regulate hSVCT1 expression in intestinal epithelial cells. Here, we investigated posttranscriptional regulation of hSVCT1 by microRNA (miRNA) in intestinal epithelial cells. A pmirGLO‐SLC23A1‐3′‐UTR construct transfected into human intestinal epithelial cells (Caco‐2 and NCM460 cells) showed significantly reduced luminescence. Bioinformatic analysis of the SLC23A1‐3′‐UTR predicted five putative miRNA binding sites (miR‐103a, miR‐107, miR‐328, miR‐384, and miR‐499‐5p) in the 3′‐UTR. Expression of mature miR‐103a was significantly higher than four other miRNA regulators in both intestinal cell lines as well as mouse jejunal mucosa. Addition of a miR‐103a mimic, but not a miR‐103a mutant construct, significantly reduced luciferase reporter activity of pmirGLO‐SLC23A1‐3′‐UTR. In contrast, addition of a miR‐103a inhibitor markedly increased luminescence. Further, addition of the miR‐103a mimic led to a marked inhibition in AA uptake, associated with decreased hSVCT1 mRNA and protein expression in intestinal epithelial cells. Reciprocally, the miR‐103a inhibitor significantly increased AA uptake, associated with increased levels of hSVCT1 mRNA and protein expression in intestinal epithelial cells. These findings demonstrate for the first time that hSVCT1 is post‐transcriptionally regulated by miR‐103a in human intestinal epithelial cells.Support or Funding InformationSupported by NIH grants DK 107474, DK 58057, DK 56057 and a grant from the DVA.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Increased HDAC9 Expression is Associated with Decreased Estrogen in Female Patients with Intracranial Aneurysm
Authors: Lansdell Theresa A , Fisher Courtney , Demel Stacie , Dorrance Anne 
Published: June 2021

Background and purposeSubarachnoid hemorrhage is a devastating consequence of intracranial aneurysm (IA) rupture. Therefore early identification of patients with IA is important. Identification of biomarkers for IA will help improve diagnosis, the understanding of IA pathogenesis, and patient management. A risk allele (rs10230207), located nearby the histone deacetylase 9 (HDAC9) gene on chromosome 7, has been associated with IA incidence. HDAC9 can repress the transcription of estrogen receptors α and β (ESR1 and ESR2). We tested the hypothesis that lymphocytes from patients with IA will have increased HDAC9 and decreased estrogen receptor gene transcription compared to controls.MethodsImmortalized B‐lymphocytes from male and female patients with un‐ruptured IA (N=109) and population controls (N=85) were obtained from the NINDS repository and cultured in RPMI‐1640 medium supplemented with 10% fetal calf serum. Subject genomic DNA was genotyped for presence of the risk allele using TaqMan SNP genotyping assays directed toward rs10230207. HDAC9 and ESR gene expression were analyzed using TaqMan expression assays. In a separate study using subject case (N=23) and control (N=10) blood samples, HDAC9 and ESR2 transcriptional differences were confirmed in peripheral blood mononuclear cells. Plasma estrogen levels were also measured in these subjects.ResultsHDAC9 expression was increased in IA patient lymphoblasts compared to population controls (P= 0.0311) and was associated with the presence of the rs10230207 risk allele (P=0. 0235). Patients harboring the risk allele had an increased risk for IA (OR 9.1, 95% CI 3.6–23.1). While the risk allele puts both males and females at risk for IA, the risk of IA is larger for females (OR 23.9, 95% CI 5.4–105.4) compared to males (OR 5.9, 95% CI 2.7–13.2). Lymphoblasts from female subjects between 19–50 years (premenopausal) were further analyzed (N= 17 cases and 22 population controls). HDAC9 gene expression was increased (P=0.0243) and ESR2 expression was decreased (P= 0.0351) in premenopausal females with IA compared to premenopausal female population controls. Decreased plasma estrogen levels were also detected in the premenopausal female cases (N=7) compared to control (N=5) subjects (P =0.0015).ConclusionsThe presence of the rs10230207 risk allele was associated with increased expression of HDAC9 and decreased expression of ESR2 in case and control immortalized lymphoblasts. Furthermore, we found that female IA patients that had not yet undergone menopause had decreased plasma estrogen levels. Future studies are aimed at defining the positive and negative predictive values of estrogen levels and IA in female patients.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Extracellular vesicles from Wistar Kyoto and spontaneously hypertensive rats have differential vasodilatory responses in resistance arteries
Authors: Good Miranda Elizabeth , Musante Luca , LaSalvia Sabrina , Carey Robert M , Howell Nancy L , Le Thu H , Erdbruegger Uta , Isakson Brant E 
Published: June 2021

Extracellular vesicles (EVs) have been described as novel bio‐markers and bio‐activators in vascular dysfunction in hypertension (HTN). However, the mechanism by which EVs affect vascular function is unknown. To examine the effects of EVs on acetylcholine (ACh)‐mediated vasodilation, we isolated 3rd order mesenteric arteries and EVs from 12‐wk old normotensive Wistar‐Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Arteries were cannulated on a pressure myograph and EVs (~6×107EV/mL) were added to the vessel lumen and circulating bath. No significant difference in ACh vasodilation was observed in control WKY and SHR arteries (no EVs). Interestingly, WKY arteries treated with WKY EVs reduced vasodilation compared to control arteries, an effect lost when treated with SHR EVs. ACh‐mediated vasodilation was not altered in SHR arteries when treated with either WKY or SHR EVs. WKY arteries treated with EVs isolated from 6‐wk old WKY and SHR, an age where SHR rats have not yet developed HTN, or with delipidated EVs from 12‐wk old WKY and SHR rats resulted in reduced vasodilation. Together, these data suggest that normotensive EVs reduce ACh‐mediated vasodilation and upon development of hypertension fail to reduced vasodilation. However, reduced vasodilation can be restored by delipidation of the SHR EVs or SHR EVs obtained prior to development of hypertension. Analysis of isolated EVs showed a larger number of CD45‐positive EVs in 12 week‐old SHR rats, indicating an increase in EVs from inflammatory cells following the development of hypertension. Using EVs isolated from human blood samples, a similar reduction in vasodilation was observed in arteries exposed to EVs isolated from normotensive humans. This effect was lost when arteries were treated with EVs isolated from hypertensive patients. This data supports the functional role of EVs in vascular regulation that is altered in HTN.Support or Funding InformationK99HL143165, K23HL12610, HL088554This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
AdipoRon, adiponectin receptor agonist, improves vascular function in the mesenteric arteries of type 2 diabetic mice
Authors: Choi Soo‐Kyoung , Kwon Youngin , Byeon Seonhee , Lee Young‐Ho 
Published: June 2021

BackgroundAdiponectin is one of the most abundant adipokines secreted from adipose tissue. An orally active synthetic adiponectin receptor agonist, adipoRon has been suggested to ameliorate insulin resistance, myocardial apoptosis, and pancreatic tumor. It has been reported that adiponectin directly induces vascular relaxation however, the chronic effect of adipoRon in the vascular dysfunction in type 2 diabetes has not been studied yet. Thus, in this study, we examined whether adipoRon improves vascular function in type 2 diabetes and what mechanism is involved.MethodsTen to 12‐week old male type 2 diabetic (db−/db−) mice were treated with adiponectin receptor agonist (adipoRon, 10 mg/kg/everyday, by oral gavage) for 2 weeks. Isolated mesenteric arteries were mounted in the arteriography and arterial diameter was measured. And western blot analysis was assessed.ResultsPressure‐induced myogenic response was significantly increased, whereas endothelium‐dependent relaxation was significantly reduced in the mesenteric arteries from type 2 diabetic mice. Interestingly, treatment of adipoRon normalized potentiated myogenic response. However, endothelium‐dependent relaxation was not affected by treatment of adipoRon. The expression levels of adiponectin receptor 1, 2 and adaptor protein phosphotyrosine interacting with PH domain and leucine zipper 1, 2 (APPL 1, 2) were increased in the mesenteric arteries from Type 2 diabetic mice and treatment of adipoRon did not affect them. Interestingly, adipoRon treatment increased the phosphorylation level of AMP‐activated protein kinase (AMPK) and decreased phosphorylation of myosin phosphatase target subunit 1 (MYPT1) in the type 2 diabetic mice while there was no change in the level of eNOS phosphorylation.ConclusionThe treatment of adipoRon improves vascular function in the mesenteric arteries from type 2 diabetic mice through endothelium‐independent mechanism. We suggest that myosin light chain phosphatase (MLCP) activation through reduced phosphorylation of MYPT1 might be the dominant mechanism in the adipoRon‐induced vascular effect.Support or Funding InformationThis work was supported by the Basic Science Research Program of the National Research Foundation (NRF) of Korea funded by the Ministry of Education, Science and Technology (NRF‐2018R1D1A1B07041820).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.