bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNA‐181a mediates neuronal differentiation and modulates microtubule stability.
Authors: Rao Anand Nandakumar , Stary Creed 
Published: June 2021

Stroke remains among the top causes of death and is the leading cause of persisting neurological disability in the United States. Treatment options remain limited to early reperfusion with thrombolysis or clot retrieval, and therapies capable of repairing damage resulting from ischemic insult are needed. Microtubules (MTs) have been recently recognized as a potential target for post‐injury therapy in the central nervous system. MTs consist of a stable and labile domain, which differ in their resistance to depolymerization, and by modulating intrinsic mechanisms that work to regulate the proportions of stable and labile MT mass in the axon, we can restore MT integrity after injury. MicroRNAs (miRNAs) are ~22‐nucleotide RNAs that regulate gene expression. MicroRNA‐181a (miR‐181a) is enriched in astrocytes, critical regulators of neuronal homeostasis and neurogenesis. Mir‐181a increases in the brain after stroke, and inhibition of miR‐181a improves functional outcomes in animal models. Using primary neuronal stem cell cultures, we demonstrate here that miR‐181a regulates neuronal differentiation. In situ analysis identified miR‐181a as a likely regulator of MT dynamics through the modulation of the MAPT (tau), MAP1B, and FIGN (fidgetin) genes. MAPT (Tau) and MAP1B are microtubule‐associated proteins (MAPs) that have been demonstrated to contribute to MT stability and neurogenesis, while fidgetin is a severing protein thought to target the labile domain of MTs and modulates a cell's ability to migrate and regulates neuronal elaboration. Therefore, we tested the hypothesis that modulation of miR‐181a activity alters MT integrity in primary neuron and astrocyte cultures and N2a cell line cultures. Immunostaining and biochemical analyses revealed injury and miR‐181a dependent changes to MAPs implicated in the modulation of microtubule stability. Overall, these results demonstrate that microRNAs can be a novel and effective target for restoring MT stability after ischemic brain injury, as well as advancing our understanding of the contributions of astrocyte regulation to increase neurogenesis and post‐injury repair after stroke.Support or Funding InformationAmerican Heart Association Fellow to Faculty Transition award: No. 14FTF19970029This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Intrathecal activation of the lectin pathway in patients with eosinophilic meningitis by Angiostrongylus cantonensis
Authors: González‐Losada Cristobal , Padrón‐González Alexander Ariel , Lumpuy‐Castillo Jairo , Rodriguez‐Pérez Alejandro , Castillo‐González William , Dorta‐Contreras Alberto Juan 
Published: June 2021

Eosinophilic meningitis produced by Angiostrongylus cantonensis is an emerging disease in Western hemisphere. MBL and H‐ and M‐ficolins are starters of the lectin pathway.ObjectiveTo determine if MBL and H‐ and M‐ficolins can be synthesizedin central nervous system in patients suffering from eosinophilic meningitis due to Angiostrongylus cantonensis.Methods19 serum and CSF paired samples were obtained from pediatric patients with the diagnosis of eosinophilic meningitis by Angiostrongylus cantonensis. Cerebrospinal fluid was obtained by lumbar puncture and serum from blood was taken by venopuncture. Serum and CSF was stored frozen in aliquots at −80°C until analysis.The local ethics committee approved this study and all patients' tutors gave informed consent.CSF and serum albumin were quantified by immunochemical nephelometry with kinetic analysis. MBL and H‐ and M‐ficolins were measured by commercial enzyme‐linked immunosorbent assay (ELISA) kit.The MBL reibergram was employed in order to determine if MBL can be synthesized inthecentral nervous system or not. The H‐ and M‐ficolins regressions were employed in order to determine if H‐ and M‐ficolins can be synthesized in the central nervous system or not.Results8 patients do not have dysfunction of blood/CSF barrier and 4 patients have intratecal synthesis of MBL.One patient do not have intrathecal synthesis of H‐ficolin (Figure 2A) and all patients have intrathecal synthesis of M‐ficolin (Figure 2B).ConclusionsIntrathecal activation of the lectin pathway by at least one of the quantified starters in this group of patients with eosinophilic meningitis due to Angiostrongylus cantonensis.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cholera Toxin Decreases SLC26A3 Expression and Function in Intestinal Epithelial Cells
Authors: Anbazhagan Arivarasu Natarajan , Coffing Hayley , Priyamvada Shubha , Kumar Anoop , Alrefai Waddah A. , Saksena Seema , Gill Ravinder K. , Borthakur Alip , Dudeja Pradeep K. 
Published: June 2021

Down‐regulated in adenoma (DRA, SLC26A3), the major Cl−/HCO3− exchanger involved in electroneutral NaCl absorption in the mammalian intestine, has emerged as a novel therapeutic target for diarrhea. Diarrhea commonly involves decreased absorption and/or increased secretion of fluid and electrolytes. We and others have shown decreased expression and function of DRA in infectious diarrhea. In this regard, cholera toxin (CTX) secreted by Vibrio cholerae is one of the most potent agents causing infectious diarrhea. Whether DRA function/expression is altered in CTX‐induced diarrhea is not known. Therefore, the current studies were undertaken to examine the effects of CTX on DRA in vitro in intestinal epithelial Caco‐2 cells. DRA function (Cl−/HCO3− exchange activity) was measured as DIDS sensitive 125I− uptake, mRNA and protein levels were assessed by quantitative real‐time PCR and immunoblotting respectively. Our results showed that treatment of Caco‐2 cells with CTX (1, 5 and 10 ng/ml) for 24 h significantly decreased Cl−/HCO3− exchange activity in a dose dependent manner. Concomitant dose‐dependent decrease in DRA mRNA levels was observed in response to CTX [1 ng/ml (46.3 ± 8.8 % p< 0.0001), 5 ng/ml (69.5 ± 3.1 % P < 0.004) and 10 ng/ml (76.5 ± 2.1%, P< 0.02)] compared to untreated control. Similarly, DRA protein levels were also significantly decreased [1 ng/ml (39 ± 15.7 5% p< 0.0001), 5 ng/ml (60.8 ± 6.3 % P < 0.0001) and 10 ng/ml (56.7 ± 12.6%, P< 0.0001)]. In conclusion, our data suggest that CTX‐induced decrease in DRA expression and function could contribute to the pathophysiology of CTX‐induced diarrhea.Support or Funding Information(Supported by NIDDK/Department of Veteran Affairs)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Slc4a8 in the Kidney: Expression, Subcellular Localization and Role in Acid Base Homeostasis and Salt Reabsorption
Authors: Xu Jie , Barone Sharon , Zahedi Kamyar , Brooks Marybeth , Soleimani Manoocher 
Published: June 2021

BackgroundThe sodium‐dependent bicarbonate transporter Slc4a8 (a.k.a NDCBE) mediates the co‐transport of sodium and bicarbonate in exchange for chloride. It is abundantly detected in the brain, with low expression levels in the kidney. The cell distribution and subcellular localization of Slc4a8 in the kidney and its role in acid/base and electrolyte homeostasis has been the subject of conflicting reports. There are no conclusive localization or functional studies to pinpoint the location and demonstrate the function of Slc4a8 in the kidney.MethodsMolecular techniques, including in situ hybridization and RT‐PCR, were performed on kidney sections and tagged epitopes were used to examine the membrane targeting of Slc4a8 in polarized kidney cells. Crispr/Cas9 was used to generate and examine Slc4a8 KO mice.ResultIn situ hybridization and Zonal distribution studies showed no expression for Slc4a8 (NDCBE) in the cortex or in cortical collecting ducts (CCD). Slc4a8 was predominantly detected in the outer and inner medullary collecting ducts (OMCD and IMCD), and was targeted to the basolateral membrane of osmotically tolerant MDCK cells when confocal microscopy images were acquired. Slc4a8 KO mice did not show any abnormal salt or bicarbonate wasting under baseline conditions or in response to bicarbonate loading, salt restriction or furosemide‐induced diuresis.ConclusionsSlc4a8 (NDCBE) is absent in the CCD and is predominantly localized on the basolateral membrane of medullary collecting duct cells. Further, Slc4a8 deletion does not cause any acid base or electrolyte abnormality in pathophysiologic states such as furosemide‐induced salt wasting or salt restriction. We suggest that Slc4a8 is likely involved in intracellular pH and volume regulation in medullary collecting duct cells.Support or Funding InformationMerit Review 5 I01 BX001000‐06 award from the Department of Veterans Affairs, and funds from the Center on Genetics of Transport and Epithelial Biology at the University of Cincinnati.
A Conserved Pain Syndrome Resulting from the Acute Activation of TrpA1 by Chemotherapy Drugs
Authors: Boiko Nina , Montano Elizabeth , Hargreaves Kenneth M. , Eaton Benjamin A. , Stockand James D. 
Published: June 2021

Treatment with anti‐cancer drugs are often compromised by a peripheral pain syndrome referred to as chemotherapy induced peripheral neuropathy (CIPN). Currently there is no treatment for CIPN and the cellular mechanisms underlying the effects of anti‐cancer drugs on sensory neuron function are not well described. Mitochondria dysfunction, axonal degeneration, reduced sensory innervation, and altered gene expression have all been observed in somatosensory neurons from animal models; but it should be noted that these outcomes are the result of prolonged systemic administration of anti‐cancer drugs and do not necessarily represent the early formative events associated with the initiation of CIPN. Here we show that acute exposure to vinca alkaloids and taxanes result in an immediate pain syndrome in both flies and mice that is consistent with the direct activation of peripheral nociceptors. Electrophysiological analyses of polymodal Class IV dendrite arborization (C4da) sensory neurons in Drosophila reveals that vinca alkaloids and taxol specifically activate the transient receptor potential cation channel A1 (TrpA1) resulting in the activation of these sensory neurons. Furthermore, TrpA1 mutant mice and flies have reduced pain in response to vinca alkaloid exposure consistent with the acute activation of TrpA1 by these chemotherapy drugs being sufficient to generate CIPN across phyla. Targeted expression of dTrpA1 in C4da neurons rescues the pain phenotype in dTrpA1 mutants. These findings represent the first demonstration of direct excitation of sensory neurons by CIPN causing chemotherapy drugs, and identify TrpA1 as an important target during the pathogenesis of CIPN.Support or Funding InformationThis work was funded by a CPRIT IIRG grant (RP150408) and a NIH/NCI R21 grant (CA194138) to J. D. Stockand and B. A. EatonThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
miR429 regulates IL‐17A expression in inflammatory monocytes in Rheumatoid Arthritis
Authors: Alpert Taylor , Rabquer Bradley James 
Published: June 2021

Rheumatoid Arthritis (RA) is a chronic, autoimmune disorder that leads to inflammation and degradation of joints. IL17A, a proinflammatory cytokine, has been previously shown to be involved in migratory inflammation pathways in autoimmune disorders like RA. IL17A initiates RA pathogenesis, suggesting that treatments targeted to neutralize IL17A would be effective therapies. Currently, anti‐IL‐17 therapies are among the most efficacious for treating RA. Additionally, studies indicate that monocytes are also causative agents of inflammation in RA. microRNAs (miRNA) have been identified as translational inhibitors in mRNA of eukaryotic cells. The relationship among monocytes, miRNAs and mRNA must be better analyzed in order to depict inflammatory pathways involved in RA. miR429 was chosen in this experiment because previous research in our lab has suggested that it is upregulated in RA monocytes. We hypothesized that the binding of miR429 to the 3′ UTR region of IL17A would down regulate the expression of IL17A and thus inflammation.Methods and ResultsGene targets involved in monocytes and inflammation were identified for miR429 in the miRNA databases miRanda and mirSVR. miR429 was found to have a relatively high binding score with IL17A. Isolating the 3′ UTR of the IL17A target gene was the first step in our series of experiments. U937 monocytes were grown and cDNA was created from isolated RNA. Primers were then designed using Primer‐BLAST program, and were created based on the hypothetical binding site on the IL17A 3′ UTR. PCR was used to amplify the 3′ UTR and a restriction enzyme digest was performed on the insert DNA and the pMirGlo vector.ConclusionOur results suggest that IL17A and miR429 are expressed by monocytes and may interact to modulate inflammation in RA.Support or Funding InformationAlbion College Biology Department and the Foundation for Undergraduate Research, Scholarly, and Creative ActivityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Biliverdin Reductase A (BVRA) Mediates the Gut Microbiome in Alcoholic liver disease
Authors: Hamoud Abdul‐rizaq 
Published: June 2021

Alcohol abuse and chronic consumption are a significant medical burden in industrialized countries. Long‐term alcohol intake is associated with changes in the intestinal microbiota that increase intestinal permeability and the release of deleterious metabolites from the gut. Alcoholic liver disease (ALD) starts with the accumulation of fats in hepatocytes that may progress to alcoholic steatohepatitis (ASH), which can further advance to fibrosis, eventually leading to cirrhosis and hepatocellular carcinoma. Plasma bilirubin levels are increased in alcoholic cirrhotic patients, which is reflective of an injurious effect to hepatocytes as a result of liver damage. In the intestine, microflora convert bilirubin to urobilinoids, which are the predominant bile pigments. We have demonstrated that a knockout of biliverdin reductase A (BVRA) in hepatocytes (hsBVRA KO) of mice, which is the enzyme that converts biliverdin to bilirubin, causes steatosis on a high‐fat diet. Recent evidence has shown that bilirubin itself is protective against hepatic lipid accumulation and obesity. We show that BVRA is suppressed in livers of mice fed alcohol. We hypothesized that BVRA is preventive of high alcohol consumption induced steatosis, which protects the liver from damage. Indeed, the hsBVRA KO mice that consume alcohol had exacerbated hepatic steatosis and changes in the gut microbiome. Together, these observations point to an early mechanism whereby high consumption of alcohol may reduce hepatic BVRA and bilirubin excretion to the gut, leading to triglyceride synthesis causing a progression toward ASH. BVRA may be a significant regulator of the gut microbiome. Future studies will investigate BVRA and bilirubin in the regulation of ALD and how they relate to the liver‐gut microbiota signaling axis.Support or Funding InformationSource of Funding: This research was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K01HL125445 (T.D.H.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High Dietary Salt Intake Drives Sympathetically Mediated Alpha‐1 Adrenoceptor Regulation of NCC to Increase Renal Sodium Retention and Blood Pressure via an OXSR1 Dependent Pathway
Authors: Puleo Franco , Frame Alissa A. , Wainford Richard D. 
Published: June 2021

BackgroundAcute studies have suggested that sympathetic nervous system (SNS) release of norepinephrine (NE) mediates upregulation of the sodium chloride cotransporter (NCC) via synergistic α1 and β adrenergic receptor pathways. Moreover, recent data suggests a key role of oxidative stress responsive 1 (OXSR1), in NCC regulation.HypothesisNorepinephrine (NE) activates an α1 adrenoceptor pathway that is dependent on OXSR1 to mediate increases in NCC activity that drive the development of salt sensitive hypertension (HTN).MethodsMale Sprague‐Dawley (SD) rats receiving a continuous s.c. saline or NE (600ng/min) infusion were fed a 0.6% (NS) or 4% NaCl (HS) diet for 14 days respectively. Separate groups of NE infused SD rats were given terazosin (10mg/kg/day; s.c.) and a NS or HS diet for 14‐days. An OXSR1 targeted lentivirus was injected in the kidneys of NE infused SD rats prior to a 14 day HS diet. On day 14 basal MAP, NCC activity (peak natriuresis to iv hydrochlorothiazide (HCTZ; 2mg/kg) infusion) and peak MAP change in response to ganglionic blockade (iv hexamethonium; 30mg/kg) were assessed. NCC expression, phosphoNCC, and OXSR1 levels were assayed via immunoblotting (N=4/gp).ResultsSD rats remain normotensive when fed a high salt diet and NCC expression and activity is downregulated. NE infusion however, inhibits the NCC downregulation associated with HS intake and evokes salt sensitive HTN. Use of an α1‐adrenoceptor antagonist in NE infused SD rats abolishes salt sensitive HTN and downregulates NCC activity. Significantly, lentiviral knockdown of OXSR1 (confirmed by immunoblot) also eliminates salt sensitive HTN in a similar fashion. Furthermore, ganglionic blockade did not produce any observable differences in NE infused rats on HS or NS that were treated or not treated with the α1‐adrenoceptor antagonist or lentivirus.ConclusionOur data reveals that SNS release of NE can modulate NCC activity via an α1‐adrenoceptor pathway to prevent dietary evoked salt sensitive HTN. Remarkably, both OXSR1 knockdown and α1‐adreoceptor antagonism reverse salt sensitive HTN. As a theoretical model, the SNS release of NE activates a linear α1‐adreoceptor pathway that stimulates OXSR1 mediated regulation of NCC. The PATHWAY‐2 Trail implicates sodium retention as a driver of resistant HTN suggesting that α1‐adreoceptor antagonism and OXSR1 blockade may represent novel therapeutic targets for HTN.Support or Funding InformationThis work was supported by NIH grants R01HL107330 and K02HL112718 and AHA grants 16MM32090001 and AHA17GRNT3367002 to RDW and NIH grant F31DK116501 to AAF.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Recovery From In Vivo Eccentric Skeletal Muscle Damage: Old versus Young
Authors: Godwin Joshua S. , Hodgman Charles F. , Rice Tyler T. , Zwetsloot Kevin A. , Shanely R. Andrew 
Published: June 2021

It has been previously reported that contractile function is depressed in old skeletal muscle, compared to young. However, to our knowledge, the recovery response of old skeletal muscle, compared to young, following in vivo eccentric skeletal muscle damage has not been previously reported. Therefore, the purpose of this study was to compare the recovery response of old skeletal muscle to young skeletal muscle following 7‐days of recovery from in vivo eccentric muscle damage. Old male mice (27.3 ± 0.2 mo) and young male mice (5.6 ± 0.1 mo) were anesthetized with isoflurane. In vivo isometric contractions (Aurora Scientific, 1300A) were performed to obtain optimal electrode placement to stimulate the anterior crural muscle group. Following electrode placement, the pre‐injury torque‐frequency relationship was established. Immediately following the pre‐injury torque‐frequency relationship, 150 eccentric contractions were elicited to induce injury. A second torque‐frequency relationship was measured immediately post‐injury to confirm damage. After 7‐days of recovery, mice were anesthetized with isoflurane and the in vivo torque‐frequency relationship was measured again. Repeated measures analysis of variance showed a significant time by group interaction (p=0.035), with no difference between groups in the torque‐frequency relationship pre‐injury (p=0.231) and a difference in the torque‐frequency relationship between groups 7‐days post‐injury (p<0.001). Further analysis revealed that the torque‐frequency relationship recovered to a greater degree in the young (p=0.313) than old (p=0.003). Analysis of a submaximal torque, i.e. 40 Hz, indicated young mice recovered 77% of initial isometric torque (p=0.254 compared to pre‐injury), while old mice only recovered 48% of initial isometric torque (p=0.003 compared to pre‐injury). Analysis of maximal tetanic torque, i.e. 250 Hz, indicated that neither young mice nor old mice recovered to pre‐injury torque output, 46% of initial (p<0.001) and 67% of initial (p=0.003), respectively. In conclusion, isometric torque decrements persist in both young and old male mice after 7‐days of recovery from in vivo eccentric muscle damage. Additionally, these data suggest that old mice exhibit a diminished capacity to recover isometric torque following eccentric damage, compared to young mice.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Knockout of Vascular Smooth Muscle Inward‐Rectifier K+ Channels Causes Symptoms of Overactive Bladder in Mice
Authors: Tykocki Nathan R. , Ross Maxwell S. , Kopec‐Belliveau Gaelin , Klinger‐Lawrence Mary Beth , Nelson Mark T. , Herrera Gerry 
Published: June 2021

The urinary bladder is highly vascularized, and chronic decreases in blood flow are linked to bladder dysfunction. Interestingly, bladder arterioles do not constrict in response to changes in intraluminal pressure (“myogenic tone”), due to a maintained membrane hyperpolarization regulated by inward‐rectifier K+ (KIR2.1) channels. We developed a tamoxifen‐inducible, smooth muscle‐specific KIR2.1 channel knockout (KIR2.1SMKO) mouse to provide additional support that vascular smooth muscle KIR2.1 channels are responsible for this lack of myogenic tone (Tykocki et al. AJP Renal Physiol, 2017). It is, however, unknown if increased vascular myogenic tone alone can alter bladder function. Unlike vascular smooth muscle, detrusor smooth muscle normally lacks functional KIR2.1 channels. Thus, we tested the hypothesis that knockout of smooth muscle KIR2.1 channels can cause bladder overactivity solely by increasing vascular tone. Voiding behavior was measured using the UroVoid® System: a novel tool for chronic, non‐invasive measurements of bladder function (void volume and frequency) in mice. At 6 weeks of age, KIR2.1SMKO mice underwent either sham surgery or surgical implantation of a 21‐day tamoxifen‐eluting pellet (10 mg/kg). Bladder function and water intake were measured before (at 4 weeks of age), during (at 8 weeks of age) and after (at 12 weeks of age) tamoxifen treatment. Prior to tamoxifen treatment, void frequency and volume did not differ between groups. At 8 and 12 weeks, sham KIR2.1SMKO mice showed an age‐dependent decrease in void frequency that correlated with an increase in void volume; this was indicative of a normal, age‐dependent increase in bladder size and voiding control. When compared to sham mice, KIR2.1SMKO mice receiving tamoxifen had increased void frequency and decreased void volume during tamoxifen treatment (8 weeks), which remained elevated at 12 weeks. This was not due to increased diuresis, as no differences in water intake were noted between groups. This suggests that increased vascular tone leads to symptoms of overactive bladder in mice, and that bladder blood flow plays an integral role in regulating bladder function.Support or Funding InformationSupported by NIH K01‐DK103840 (NRT) and R37‐DK053832 (MTN).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.