bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eicosapentaenoic Acid Prevents Obesity‐induced Metabolic Impairments through The Host‐genetic Dependent Effects of Resolvin E1
Authors: Pal Anandita , Al-Shaer Abrar E. , Guesdon William , Torres Maria J. , Armstrong Michael , Quinn Kevin , Reisdorph Nichole , Neufer P. Darrell , Shaikh Saame Raza 
Published: April 2020

Eicosapentaenoic acid (EPA) is a n‐3 polyunsaturated fatty acid that is poorly consumed in the western diet. Increased EPA consumption has been reported to improve glucose and insulin homeostasis in rodent models. We demonstrate that administration of pure EPA ethyl esters to C57BL/6J male mice improved obesity‐induced glucose intolerance, hyperinsulinemia, and hyperglycemia. Analyses of National Health and Nutrition Examination Survey data also revealed fasting glucose levels of obese adults to be inversely related with EPA intake in a sex‐dependent manner. To investigate potential mechanisms by which EPA improved glucose homeostasis, we compared rodent models consuming a control and a high fat diet in the presence or absence of EPA. 16S rRNA sequencing demonstrated that EPA supplementation was not associated with an improvement in the murine gut microbiome composition. Subsequent untargeted and targeted mass spectrometry analyses revealed distinct modifications to the lipidome. Notably, EPA dramatically enhanced the levels of 18‐hydroxyeicosapentaenoic acid (18‐HEPE) in the heart, white adipose tissue, and liver. Therefore, we investigated if administration of the downstream bioactive metabolite of 18‐HEPE, resolvin E1 (RvE1) could improve hyperinsulinemia and hyperglycemia. We also determined if these effects were mediated through the RvE1 receptor ERV1/ChemR23. RvE1 administration to obese mice mitigated hyperinsulinemia and hyperglycemia in a manner that was dependent on ERV1/ChemR23, as revealed with ERV1/ChemR23 knockout mice. Finally, we assessed if the host genome altered the metabolic outcomes of RvE1. Secondary SNP analyses revealed extensive genetic variation in human EPA and RvE1 metabolizing genes. RvE1’s effects on fasting insulin and glucose were divergent in diversity outbred mice that model human genetic variation. In conclusion, increased intake of EPA ethyl esters prevent obesity‐induced metabolic impairments through RvE1 binding to ChemR23. The data also underscore the critical need for precision prevention studies that account for host‐genetic variants in the EPA‐RvE1 axis.Support or Funding InformationR01AT008375 (SRS), P30DK05635 (SRS), NIH/NCRR S10 RR026522‐01A1 (NR), R01DK096907 (PDN)
Defining roles of the sterol recognition region in Hedgehog cholesterolyation
Authors: Purohit Rahul , Vielmas Erika , Peng Daniel S. , Ondrus Alison 
Published: April 2020

The Hedgehog (Hh) signaling pathway plays an essential role during embryogenesis and when dysregulated, can lead to human cancer (basal cell carcinomas) and the most lethal form of juvenile medulloblastoma. Binding of the Hh ligand to its receptor Patched (Ptch) relieves inhibition of the GPCR protein Smoothened (Smo) leading to activation of the Gli transcription factors and changes in target gene expression. The Hh ligand is decorated with two covalent modifications, N‐terminal palmitoylation and C‐terminal cholesterolyation. Hh proteins are synthesized as approximately 45 kDa full‐length species, whereupon a unique process yields the mature morphogen: an autocatalytic cleavage that splits the protein in two and attaches cholesterol to the newly formed C‐terminus. Of the two approximately equal molecular weight cleavage products, the dually lipidated N‐terminal fragment (Hh‐N/“Hog” domain) constitutes the classical Hh morphogen, whereas the C‐terminus (Hh‐C/“Hint”) is responsible for the cleavage reaction.In order to elucidate the chemical mechanism of cholesterolyation, we have determined the roles of the previously uncharacterized sterol recognition region (SRR) in Hh proteins. Using bioinformatics, alanine scanning, and biochemical assays we have identified key motifs and specified residues of the SRR that are required for biochemical processing of Hh. These results provide a first in detail insights into the role of this unique small region of the Hh protein that is capable of cellular targeting and engaging cholesterol to generate an active Hh ligand.Support or Funding InformationThis work was supported by the Margaret E. Early Medical Research Trust.
Selective Stimulation of Vagal Pathways Using a Multi‐contact Circumferential Cuff Electrode
Authors: Shulgach Jonathan A. , Nanivadekar Ameya C. , Miller Derek , Fulton Stephanie , Sciullo Michael , Ogren John , Wong Liane , McLaughlin Bryan , Yates Bill J. , Horn Charles C. , Fisher Lee E. 
Published: April 2020

Vagus nerve stimulation (VNS) has been used to treat epileptic seizures, depression, cardiovascular disease, and obesity; however, non‐selective vagal stimulation can produce adverse side effects, such as nausea and reduced blood pressure. The current study was designed to assess the potential for a precision, multi‐contact nerve cuff electrode to produce selective and discrete activation of vagus nerve fibers. We used an acute anesthetized ferret preparation (n = 6) to test the effects of an abdominal vagus nerve electrode (Micro‐Leads Neuro) on cellular responses (compound action potential, CAP) recorded from a 32‐channel microelectrode array (MEA) inserted into the nodose ganglion. We investigated the selectivity of nodose responses by varying: (1) electrode contact stimulation pair; (2) pulse width, using 0.1, 0.5, and 1.0 ms; and (3) pulse amplitude, steps of 20 μA. Stimulation was delivered at 2 Hz using the average response from 120 pulses per trial. Selectivity was quantified by the number of MEA channels responding to only one of the two cuff stimulation pairs. Across all animals, stimulation selectively evoked responses recorded by multiple different contacts in the MEA. In a similar experimental setup in three additional animals, multi‐contact stimulation of the abdominal vagus was used to drive changes in gastric myoelectric activity (GMA), as assessed by a set of four to six 4‐contact electrode planar arrays (Micro‐Leads Neuro) sutured to the serosal surface of the stomach. In one animal, selective stimulation drove changes in GMA without a concomitant change in heart rate (HR) or respiration rate (RR), while in two other animals, there was a selective change in HR or RR without a change in GMA. The present study supports the viability of producing selective responses from multi‐contact abdominal vagus nerve cuff electrodes and suggests the need to further investigate the effects of selective VNS on end‐organ therapeutic and off‐target effects, such as gastrointestinal motility, heart rate, blood pressure, inflammatory responses, and metabolic effects (e.g., blood cytokine levels and insulin release).Support or Funding InformationThis research was supported by funding from the NIH SPARC Common Fund Program (award #U18TR002205).
Aged Plasma and Plasma‐Derived Factors Drive Detrimental Effects in the CNS of Young Mice
Authors: Le David , Liu Angela , Campbell Meghan K. , Yang Cindy , Minami S. Sakura , Braithwaite Steven P. , Czirr Eva 
Published: April 2020

Aging results in cognitive decline and molecular changes that contribute to the risk of developing aging‐associated disease. As the aging population is rapidly increasing, with those over 60‐years‐old set to double by 2050, there is urgent need for a better understanding of the aging process and development of therapeutics for diseases of aging. Recent publications have shown that some aging‐associated phenotypes can be driven by plasma and plasma‐derived factors. In these studies, we sought to identify and validate detrimental effects of aged plasma and plasma‐derived factors on cognitive, histological, and molecular readouts in order to discover novel therapeutic targets for age‐related diseases. Our data show that administration of aged human plasma into young immunodeficient NSG (NOD.Cg‐Prkdcscid Il2rgtm1Wjl/SzJ) mice results in a decrease in neurogenesis and mild impairment in cognition. These results indicate that factors in aged human plasma can drive detrimental effects in the brains of young NSG mice. Plasma proteomics have identified aging signatures and specific proteins that are potential drivers of these negative effects in aging, and beta‐2 microglobulin (B2M) has been shown to be a pro‐aging factor with deleterious effects on cognition and neurogenesis. To confirm B2M as a negative factor, we treated young mice (WT; C57BL/6J) with recombinant human B2M and assessed changes in behavioral performance and histological markers. We found that systemic administration of B2M resulted in cognitive impairment during contextual fear conditioning and decreased neurogenesis, suggesting that it is a driver of negative effects during aging. Our data elucidate molecular pathways that contribute to the aging process and provide promising targets for developing translational therapeutics.Support or Funding InformationStudies were funded by Alkahest.
Measuring Airway Resistance and Characterizing the Flow‐Volume Envelope with External Expiratory Loading in Healthy Adults
Authors: Erram Jyotika , Bari Monica , Cannon Daniel 
Published: April 2020

Expiratory flow limitation is a key characteristic in chronic obstructive pulmonary disease (COPD). Increased airway resistance occurs due to bronchoconstriction, destruction of elastic tissue in the airways, and mucus hypersecretion from goblet cells caused by irritation of the epithelium. Obstruction can lead to dynamic hyperinflation, dyspnea, and exercise intolerance. However, increased airway resistance is just one of many abnormalities in COPD and asthma ‐ COPD in particular is an exceedingly heterogeneous disease. Therefore, isolating the effects of expiratory airflow limitation is challenging.PURPOSEIn order to study abnormal lung mechanics in isolation, we measured pulmonary function with and without expiratory loading in healthy adults.METHODSForty‐eight volunteers (26±5 yr, 171.8±10.2 cm, 72.2±13.3 kg) completed spirometry and body plethysmography according to the ATS/ERS standards under three randomized conditions: control, expiratory loading of 7 and 11 cmH2O. The expiratory load was added by installing a threshold inspiratory muscle trainer in reverse. We analyzed the shape of the flow‐volume (F‐V) loops with rectangular area ratio (RAR) using custom MATLab software.RESULTSAirway resistance was increased (F[1.5, 27.5]= 446.0, p<0.05) with 7 and 11 cmH2O vs control (9.20±1.02 and 11.76±1.68 cmH2O vs. 2.53± 0.80 cmH2O). RAR (F[1.9, 77.9]= 3.71, p>0.05) was reduced with 7 and 11 cmH2O vs control (0.45±0.07 and 0.47±0.09L vs. 0.48±0.08L). FEV1 was reduced (F[1.6, 60.38.6]= 67.54, p<0.05) with 7 and 11 cmH2O vs control (3.26±0.82 and 3.23±0.79L vs. 4.03±1.04L). FVC was also reduced (F[1.5, 55.31] = 77.71, p<0.05) with 7 and 11 cmH2O vs control (4.15±1.01 and 4.17±1.02L L vs. 5.05±1.33L L). PEF was reduced (F[1.5, 55.99] = 72.69, p<0.05) with 7 and 11 cmH2O vs control (6.02±1.65 and 5.95±1.85L vs. 8.39±2.85L L). FEV1/FVC (F[1.9, 69.17] = 5.5, p> 0.05) and FRC (F[1.863, 33.53]= 0.93, p<0.05) were not different between resistance conditions or compared to the control.CONCLUSIONSExpiratory loading reduced FEV1, FVC, PEF and provided a doseresponse in airway resistance and RAR. There were no differences in FEV1/FVC. While RAR was reduced with expiratory loading, the magnitude was of little clinical importance. Therefore, a concave expiratory F‐V relationship was consistently absent – a key limitation for model comparison with pulmonary function in COPD. This is most likely due to the imposed resistance being applied outside of the airways, leading to higher airway pressures. The higher airway pressures are likely to resist dynamic airway compression and either maintain the equal pressure point position or possibly move it proximally.
Exercise Training Attenuates Sarcopenic Obesity‐Induced Insulin Resistance and Mitochondrial Dysfunction in the Rat Skeletal Muscle
Authors: Kwak Hyo-Bum , Heo Jun-Won , No Mi-Hyun , Cho Jin-Kyung , Choi Young-Ju , Cho Eun-Jeong , Chang Eun-Wook , Park Dong-Ho , Kang Ju-Hee , Jang Young Charles 
Published: April 2020

The purpose of this study was to determine the effects of sarcopenic obesity (aging‐induced sarcopenia plus high fat diet‐induced obesity) and exercise training on insulin resistance, mitochondrial function (hydrogen peroxide (H2O2) emission and calcium(Ca2+) retention capacity) and mitochondrial dynamics (fusion; Opa1, Mfn1, Mfn2 and fission; Drp1, Fis1) in the rat skeletal muscle.Sprague‐Dawley rats were randomly divided into four groups: 4‐month young control (YC), 20‐month old control (OC; sarcopenia), old high fat diet group (OH; sarcopenic obesity), and old high fat diet and exercise group (OH+EX). After obesity was induced by 7 weeks of 60% high fat feeding in old groups, treadmill exercise was performed 6 times a week for 7 weeks. Oral glucose tolerance test was performed to determine insulin resistance. Mitochondrial function (H2O2 emission, Ca2+ retention capacity) was measured in permeabilized skeletal muscle (soleus and white gastrocnemius). Also, mitochondrial dynamics (fusion and fission) were analyzed using Western immunoblot in skeletal muscle.Insulin resistance was induced in OC and OH compared with YC. Conversely, insulin resistance was mitigated in OH+EX compared with OC and OH. Excessive mitochondrial H2O2 emission was found in white gastrocnemius of OC and OH compared with YC. However, exercise training attenuated aging and obesity‐induced mitochondrial H2O2 emission in OH+EX compared with OC and OH. Although mitochondrial Ca2+ retention capacity was not significant between groups in type I muscle (soleus), it was dramatically downregulated by aging and obesity and conversely upregulated by exercise training in type IIb muscle (white gastrocnemius) in OH+EX compared with OC and OH. In addition, exercise training protected against the imbalance between mitochondrial fusion and fission, showing that aerobic exercise training improved aging and obesity (sarcopenic obesity)‐induced decrease in Opa1 and Mfn2 protein levels and, conversely, reduced the increase in Drp1 and Fis1 protein levels in type IIb muscle in OH+EX compared with OC and OH.Our data demonstrated that sarcopenic obesity induced more insulin resistance, mitochondrial dysfunction, and mitochondrial remodeling than sarcopenia in skeletal muscle. However, exercise training mitigated sarcopenic obesity‐induced impairment in insulin resistance and mitochondrial function in skeletal muscle, suggesting that aerobic exercise training plays an essential role in attenuating sarcopenic obesity‐induced insulin resistance through the regulation of mitochondrial function in the skeletal muscle.Support or Funding InformationThis work was supported by the Ministry of Education of the Republic of Korea and the National Research Foundation (2018R1A2A3074577, 2019S1A5C2A03082727).
Hosta longipes and its Active Compounds Control Melanogenesis in B16F10 Melanoma Cells
Authors: Sohn Eun-Hwa , Kim Sung Hyeok , Ha Chang Woo , Lee Jinwoo , Kim Youngseok , Chae Doobyeong , Sung Sikwon , Ham Jungyeob , Kim Su-Nam 
Published: April 2020

Hosta longipes (FR. et SAV.) MATSUMURA (Liliaceae) is an edible vegetable in Korea and widely distributed throughout Korea, China, and Japan. It is called “Bi‐Bi‐Chu” in Korea, and its young leaves are consumed raw as a salad. This plant has been used as a Korean traditional medicine for the treatment of swelling, inflammation and snake bites. In this study, we confirmed the whitening effects of Hosta longipes ethanol extract in B16F10 cells and identified that hexane fraction had the highest whitening effect by serial solvent fractionation. To identify the active ingredients in the hexane fraction we performed column chromatography and it was confirmed that linolenic acid and linoleic acid reduced the melanin contents in B16F10 cells. The anti‐melanogenesis potential of linolenic acid and linoleic acid in Hosta longipes will provide insight into the development of new skin whitening products.Support or Funding InformationThis research was financially supported by the Ministry of Small and Medium‐sized Enterprises(SMEs) and Startups(MSS), Korea, under the “Regional Star‐Enterprise Development Program(R&D, P0010100)” supervised by the Korea Institute for Advancement of Technology(KIAT)
Mechanisms for Temporal Information Coding in Inflammatory JNK Signaling
Authors: Tomida Taichiro , Yamaguchi Kimitaka , Ito Masanori , Mikami Yoshinori , Ohshima Daisuke , Adachi-Akahane Satomi 
Published: April 2020

JNK (c‐Jun‐N‐terminal kinase) is a stress‐activated protein kinase that plays key roles in mediating stress and inflammatory response such as cell death, proliferation, and cytokine production. Several studies have uncovered that the duration of JNK signaling determines the specificity of downstream cellular events that lead to either cell‐death or survival. However, the question of how JNK is dynamically regulated in cells remains elusive. In this study, we aimed to reveal the physiological importance of the dynamics of JNK signaling in downstream gene expression by elucidating how inflammatory cytokine IL‐1β regulates a temporal pattern of JNK signaling in living HeLa cells. Here, using fluorescence imaging and our novel JNK activity reporter based on FRET, we succeeded in the quantitative evaluation of JNK dynamics at single cell resolution upon IL‐1β stimulation. Periodic pulsatile IL‐1β‐stimuli to cells were employed to analyze the regulatory mechanism of JNK activity. Our analysis revealed that JNK can be activated either transiently or repeatedly depending on the interval of stimulation pulses, while the initial peak amplitude of JNK activity was almost the same. We found that a simple negative‐feedback loop from a MAPK phosphatase MKP1 to its upstream kinase p38 MAPK accounts for the observed temporal dynamics of JNK activity, which was further verified by biochemical analysis and mathematical model simulation. The temporal aspects of IL‐1β stimulation were reflected in the gene expression profile obtained from HeLa cells after stimulation, in which the specific set of JNK‐dependent genes were more upregulated by repetitive IL‐1β stimulation pulses compared to that by continuous IL‐1β exposure. Our results indicate that the dynamic behavior of JNK in response to IL‐1β stimulation is regulated through dephosphorylation of JNK by MKP1 whose expression is positively regulated by p38 MAPK and down‐regulated by its phosphatase activity on p38 MAPK. In addition, JNK activity as well as downstream gene expression specificity could be modulated just by altering the temporal pattern of input IL‐1β stimuli. In conclusion, we demonstrated that the information of temporally fluctuating cytokine stimulation can be converted into the activation dynamics of JNK signaling, and the downstream gene expression specificity can be encoded by the temporal dynamics of JNK activity. Such a temporal information coding mechanism may have physiological relevance for inducing an adequate cellular response to a wide range of fluctuating cytokine levels through precise control of gene expression.Support or Funding InformationThis work was supported in part by JSPS KAKENHI [Grant numbers JP19K06548, JP17H06017 to T.T., JP18K06859 to S.A‐A.].
The expression of TMEM16 scramblases in the neurovascular unit
Authors: Lee Byoung-cheol 
Published: April 2020

Biological membranes, composed of a double layer of lipids, define the boundaries of living cells and their subcompartments. In eukaryotes, the outer and inner leaflets of the plasma membrane differ in their lipid compositions, with the outer leaflet containing mostly phosphatidylcholine (PC) and sphingolipids, while the inner leaflet is composed of phosphatidylethanolamine (PE), the negatively charged phosphatidylserine (PS), and phosphoinositides. Two classes of ATP‐driven pumps, flippases and floppases, create and maintain the membrane asymmetry, whose rapid collapse occurs during a process called phospholipid scrambling. Members of the TMEM16/ANO family of membrane proteins are Ca2+‐activated phospholipid scramblases and/or Cl− channels. As phospholipid scramblases, they generate key physiological signal by translocating phosphatidylserine (PS), an effector in numerous cell activities such as blood coagulation and the phagocytic clearance of apoptotic cells. Here, we investigated the expression profile of each TMEM16 scramblase in the neurovascular unit (NVU). NVU is a complex functional and anatomical structure composed of endothelial cells, pericytes, smooth muscular and neural cells, including astrocytes, neurons, and interneurons. Also, we investigated the expression of TMEM16 in various brain regions such as cerebral cortex, hippocampus, hypothalamus, medulla, midbrain, etc. The studies on the expression profile of TMEM16 would enhance our understanding the physiological roles of specific TMEM16 scramblase in NVU.Support or Funding InformationThis research was supported by KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT(20‐BR‐01‐07) and National Research Foundation of Korea (NRF) grant funded by the Korea government(MSIT) (2019R1C1C1002699)
Investigating the Mechanisms Underlying the Link Between Diabetes and Cancer
Authors: Minch Benjamin , Englund Dylan , Sterken Crystal , LaBounty Zachary , Kim Jinsil 
Published: April 2020

Diabetes is one of the most common diseases, with its prevalence having increased significantly over the last two decades. A growing number of evidence indicates a higher risk of cancer among patients with diabetes, but the mechanisms underlying the link between diabetes and cancer remain elusive. Hyperglycemia (high blood glucose levels) is a key metabolic abnormality that characterizes diabetes, and could potentially play a role in the pathogenic process of cancer. This study aims to investigate the effects of hyperglycemic conditions on cancer development and progression. The results of cell proliferation assays support cancer‐promoting effects of hyperglycemic conditions in SW620 colorectal cancer cells. High‐glucose treatments, however, did not have any effect on the rate of apoptotic cell death. Analysis of selected RNA‐binding proteins (RBPs) revealed expression changes of the RBPs involved in the methylation of adenosine at the nitrogen‐6 position (N6A) in RNA in response to elevated glucose levels. In line with these changes, there were alterations in N6‐methyladenosine (m6A) levels in high glucose‐treated SW620 cells compared to control cells exposed to normal glucose conditions. Our study also suggests that hyperglycemia causes oxidative stress through the production of reactive oxygen species (ROS). Given that elevated levels of ROS and m6A RNA methylation have been significantly implicated in human cancer, oxidative stress and altered m6A levels caused by dysregulation of the RBPs involved in m6A modification may play, at least, a partial role in diabetes‐induced cancer, which warrants future exploration. Collectively, our study provides potentially important insight that could add to the understanding of the mechanisms explaining the link between diabetes and cancer.Support or Funding InformationThis work was supported by the Stewart Science Honors Program, the School of Science, Technology and Health, and the Department of Biological Sciences at Biola University, CA, USA.