bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Iron Metabolism for Colorectal Cancer Treatment
Authors: Xue Xiang , Shah Yatrik 
Published: June 2021

Hypoxia is a key feature of most solid tumors including colorectal cancer (CRC). Hypoxia‐inducible factors (HIFs) are the major transcription factors that respond to hypoxia and are essential for tumor survival and growth. However, the main downstream pathways of HIF‐mediated tumor growth are not clear. We show that HIF‐mediated dysregulation of intratumoral intestinal iron homeostasis through induction of the iron uptake transporter divalent metal transporter 1 (DMT1) and a ferrireductase six‐transmembrane epithelial antigen of prostate 4 (STEAP4) is a major mechanism leading to CRC. Decreasing intratumoral iron by low iron diet or germ‐line Dmt1 knockout inhibits, whereas genetic overexpression of STEAP4 promotes CRC progression. If this is a druggable pathway and could serve as a therapeutic method for CRC is not known. We generated a mouse model with a temporal and conditional disruption of Dmt1 gene in the intestine (VilERT2 Dmt1F/F) by crossing Dmt1F/F mice with Villin‐CreERT2 transgenic mice, carrying a tamoxifen‐inducible Cre. Colorectal tumors were first established in this mouse model by one dose of azoxymethane (AOM) and three cycles of 1.5% dextran sulfate sodium (DSS), and then mice were treated with three daily doses of 100 mg/kg tamoxifen to disrupt Dmt1 in established colorectal tumor epithelium. One month later tumor number, tumor size at 2–3 mm and 3–4 mm, and tumor burden were significantly reduced in VilERT2 Dmt1F/F mice compared to their littermate control (Dmt1F/F). Consistent with the findings in human CRC, the gene expression of Dmt1 was increased in the tumor tissues compared to normal adjacent tissues in littermate control mice, and significantly decreased in both normal and tumor tissues in VilERT2 Dmt1F/F mice. Immunofluorescence staining revealed that cell proliferation, as determined by bromodeoxyuridine (BrdU) and Ki67 staining, was not changed, but cell apoptosis assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and cleaved caspase 3 (cCasp3) staining was increased in colorectal tumor tissues from VilERT2 Dmt1F/F mice compared to control mice. In addition, tumor vascularization and macrophage infiltration were not altered. These results demonstrate that Dmt1 is critical for tumor growth in the AOM‐DSS‐induced mouse colitis‐tumor model, and targeting iron metabolism is a feasible strategy for CRC treatment.Support or Funding InformationX.X. was supported by NIH Grant 1K01DK114390‐01 and a Research Scholar Award from the American Gastroenterological Association. Y.M.S. was supported by NIH Grants CA148828 and DK095201.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Quantification of Striatal Dopamine Receptors in a Monogamous Bird
Authors: Eisenman Lauren Elizabeth , Coleman Melissa 
Published: June 2021

Little is known about the neural mechanisms that underlie monogamous behavior. In this study, dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) reorganization in the nucleus accumbens and other striatal tissue was evaluated as a possible physiological basis of monogamous behaviors. Previous research in a monogamous mammal, the prairie vole, has shown that striatal D1R activation is implicated in maintaining pair‐bonds, and is upregulated in pair‐bonded voles versus un‐pair bonded voles. The same research team showed that D2R activation plays an important role in forming the pair‐bond, however there was no significant increase in D2R in pair‐bonded voles versus monogamously naïve voles (Aragona et al., 2006). Dopamine is also implicated in a monogamous bird, the zebra finch (Taeniopygia guttata); after pair‐bonding, dopamine levels rise in the nucleus accumbens (Banerjee et al., 2013). Furthermore, previous research in the Coleman lab has shown that D2R activation by a systemic, subcutaneous D2R agonist can induce a partner preference in finches, like in prairie voles. These similar underpinnings with the D2R indicate that D1R upregulation may also occur in zebra finches. To determine if there is D1R upregulation in zebra finches, we used quantitative real‐time PCR to quantify striatal D1R and D2R expression in pair‐bonded and un‐pair bonded birds, as well as in naïve birds that were directly infused with a D2R agonist in the ventral medial striatum, the location of the nucleus accumbens. We found no statistically significant upregulation of either D1R nor D2R between pair‐bonded and naïve birds. However, there was an upregulation of D2R in the upper striatum of birds that were directly infused with D2R agonist. Furthermore, we found an upregulation of tyrosine hydroxylase (TH), a precursor enzyme in the production of dopamine, in striatal tissue of pair‐bonded birds. These findings suggest that zebra finches may not rely on physiological reorganization of dopamine receptors, but instead on increased dopamine levels in the ventral medial striatum created by an upregulation of TH.Support or Funding InformationAPS IOSP Undergraduate Summer Research Fellowship IOS‐1238831This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cortactin's Influence on Mitochondrial Bioenergetics in the Diabetic Heart: A Novel Viewpoint
Authors: Durr Andrya Jean , Shepherd Danielle Lee , Hathaway Quincy Alexander , Hollander John Michael 
Published: June 2021

Cortactin, a protein which controls the cytoskeleton, has been suggested to impact mitochondrial function by influencing the outer mitochondrial membrane during fusion and fission. Cortactin has been shown to interact directly with Coronin 1b by affecting Arp 2/3 during actin formation and branching, but it is currently unknown how cortactin dynamics affect the structure and function of mitochondria in the heart during type 2 diabetes mellitus. The goal of the study was to visualize changes in cytoskeletal proteins in the type 2 diabetic heart, and determine whether genetic alteration of cortactin levels impacts the mitochondrion on a molecular level. We hypothesized that cytoskeletal proteins associated with mitochondrial dynamics would be significantly altered in the type 2 diabetic state, and that specific changes in cortactin would have a direct effect on mitochondrial bioenergetics and function. Western blots were utilized to visualize cortactin, coronin1b and phosphor‐coronin1b levels in type 2 diabetic human patient heart and db/db mouse cardiac tissue. Results indicated that in both type 2 diabetic human patient and db/db cardiac tissue, cortactin and coronin1b levels are dysregulated. Cortactin levels were significantly increased (P<0.05) as were coronin1b levels in db/db mouse cardiac tissue (P<0.05). Phosphorylated coronin1b was significantly decreased in human type 2 diabetic cardiac tissue (P<0.05). To determine whether increased cortactin levels observed in the type 2 diabetic state can influence the mitochondrion, we utilized an HL‐1 cardiomyocyte model in which cortactin was either knocked down or overexpressed. Mitochondria were isolated post transfection with an expression vector for cortactin and analyzed via flow cytometry for size and internal complexity, JC‐1 staining for membrane potential, electron transport chain complex activities, and bioenergetics using the Seahorse. Cortactin overexpression and knockdown significantly altered the membrane potential of the mitochondria (P<0.05). Further, in cells overexpressing cortactin, exogenous fatty acid utilization was decreased (P<0.05), and cells appeared to be completely dependent of endogenous free fatty acids (FFA) for respiration (P<0.05). Taken together, our data indicate that cortactin is significantly increased in the type 2 diabetic heart of both human patient and mouse cardiac tissue. Further, these data indicate that increased cortactin levels associated with the type 2 diabetic heart may contribute to changes in mitochondrial function by influencing membrane potential and their capacity to utilize FFA during respiration.Support or Funding InformationSupport: NIH R01 HL128485; AHA 17PRE33660333This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Daily and seasonal rhythms of interleukin 6 and cortisol levels in saliva and some lifestyle habits of medical students in Poland
Authors: Kanikowska Dominka , Rutkowski Rafał , Sikorska Dorota , Orzechowska Zofia , Sato Maki , Brêborowicz Andrzej , Witowski Janusz 
Published: June 2021

ObjectiveA primary aim of this study was to establish possible daily and seasonal rhythms of interleukin 6 and cortisol in the saliva using 15 healthy female volunteers.MethodsAll of the females were at the same stage of their menstrual cycle (follicular or luteal) during the two seasons tested. Twelve saliva samples were taken at 20 h, 22 h, 24 h, 02 h, 04 h, 06 h, 08 h, 10 h, 12 h, 14 h, 18 h and 20 h the next day, during one of the days of the two seasons tested (in January/February and May/June). Additionally, each subject filled out a questionnaire regarding her lifestyle habits. The volunteers answered questions regarding their sleep time, food and fluid intake, and the amount of physical activity undertaken on a weekday and weekend of each season tested. The study adhered to the Principles of the Declaration of Helsinki.ResultsThere is a statistical difference between cortisol concentrations during the seasons, with a higher level of cortisol during the summer. However, there was no statistical significance regarding the concentration of interleukin 6. A significant positive correlation between the increased physical activity and the knowledge regarding a healthy lifestyle was found (P = 0.005).ConclusionsThis study indicates that cortisol concentration in the saliva shows statistically significant differences between the seasons. Some aspects of lifestyle, especially related to sleep and eating patterns, differ significantly between weekdays and weekends.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
UCHL1 regulates Interleukin‐6 expression in skeletal muscles
Authors: Li Yifan , Gao Hongbo , Wu Penglong , Wang Xuejun 
Published: June 2021

Chronic low grade inflammation is a hallmark of aging and has been linked to aging related dysfunction and disease. As the largest tissue mass, skeletal muscles express and release several inflammatory cytokines including interleukin‐6 (IL‐6). With altered function and metabolism, aged muscles can be a major source of inflammatory cytokine in aging. Ubiquitin C‐terminal Hydrolase L1 (UCHL1) was originally found in the brain. Our recent study revealed that UCHL1 is inducible and upregulated in skeletal muscles in mice by denervation and lipopolysaccharide (LPS). In differentiated C2C12 cells. UCHL1 gene knockdown using siRNA significantly increased Interleukin 6 (IL‐6) level in the media. Consistent with this in vitro data, the plasma level of IL‐6 was also higher in mice with global or muscle specific UCHL1 gene knockout. Moreover, UCHL1 gene knockdown in C2C12 significantly reduced the protein level of IκB, a key inhibitory molecule for the activation of NF‐kB signaling pathway. Reduced protein level of IκB was also observed in muscles from UCHL1 knockout mice. These data suggest a potential novel mechanism by which UCHL1 controls IL‐6 expression in skeletal muscle by stabilizing IκB and thus inhibiting activation of NF‐kB pathway. Given the impaired UCHL1 function in the brain with aging, it is plausible to hypothesize that aging may also reduce the UCHL1 control of NF‐kB activation in skeletal muscle, leading to muscle‐derived chronic inflammation in aging.Support or Funding InformationThis study is supported by NIH grant 1R15HL118696 and 1R03AG051926, the USD BBS graduate program, USD CBBRe pilot grant, and USD PQCD pilot grant.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Liposomal Delivery of miR‐29b Restored PRMT ‐1 and PRMT‐5 Expression and Histone Methylation in Mice Exposed to Perinatal Inflammation
Authors: Sugar Sophia S. , Heyob Kathryn M. , Lee Robert M. , Rogers Lynette K. 
Published: June 2021

BackgroundBronchopulmonary dysplasia (BPD) continues to be a significant pulmonary complication for preterm infants, but the mechanisms associated with altered lung development remain poorly understood. Our mouse model of perinatal inflammation mimics the pathophysiology observed in infants with severe BPD. We have previously reported decreased pulmonary miR‐29b expression, and that restoration of miR‐29b expression improves lung development. The current studies tested the hypothesis that decreased expression of miR‐29b was associated with decreases in expression of key protein methyltransferases (PRMTs), and that restoration of miR‐29b would restore expression.MethodsPregnant C3H/HeN mice received an intraperitoneal LPS injection on E16 and newborn pups were exposed in 85% oxygen from birth to 14 days of life. On postnatal day 3, PBS containing a liposomal preparation of miR‐29b or an empty liposome was administered intranasally. On postnatal 28, mouse lung tissues were analyzed for changes in PRMT‐1, PRMT‐5, and symmetrical and asymmetrical dimethylation of histone 4, arginine 3 by western blot.ResultsPerinatal inflammation resulted in decreased expression of PRMT‐1 and PRMT‐5 which led to a decrease in histone 4, arginine 3 symmetrical dimethylation. Liposomal delivery of miR‐29b restored PRMT‐1 and PRMT‐5 expression and partially attenuated the decrease in histone 4 symmetrical methylation.ConclusionOur data suggest that restoration of miR‐29b may prevent aberrant expression of matrix proteins by increasing histone 4, arginine 3 dimethylation and promoting gene silencing.Support or Funding InformationThe authors gratefully acknowledge funding from the NIH/NICHD R01HD0880833This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Novel role of CREB in regulating maturation of alveolar macrophages and thereby in maintaining lung‐fluid balance
Authors: Rochford Ian P. , Joshi Jagdish P. , Mehta Dolly P. 
Published: June 2021

Alveolar macrophages (AM) represent a specialized subpopulation of lung resident macrophages responsible for coordinating both the initiation and resolution of inflammatory lung injury. Analysis of the dynamics of lung resident macrophage populations using LyzM‐GFP mice (green myeloid cells) over the course of five days post‐injury by nebulized LPS showed a gradual decline in AM during injury phase but AM expanded and returned to baseline levels by 5th day post injury. While evidence suggests that recruited bone marrow monocytes can adopt AM phenotype following their differentiation into interstitial macrophage mechanisms reconstituting AM remains elusive. CREB, a cAMP‐Response Element Binding protein, is known to transcribe genes which regulate several cellular processes including cell differentiation, angiogenesis and anti‐inflammatory signaling. Mice lacking CREB rapidly die after birth primarily due to impairment of lung function. Thus, we generated mice lacking CREB in myeloid cells (CREBΔMye) by crossing CREBfl/fl mice with LyzM‐Cre mice to test the hypothesis that CREB regulates AM generation and thereby maintains lung‐fluid homeostasis. We show that in contrast to CREBfl/fl mice, CREBΔMye lungs developed lung edema basally. LPS induced significantly more edema formation at 4h in CREBΔMye than control mice. Whereas the edema resolved fully in control mice at 24h CREBΔMye lungs remained edematous. FACS analysis showed ~50% reduction in AM in CREBΔMye lungs (SiglecF+/CD11b‐/CD11c+ cells) basally and at 24 h following LPS‐induced lung injury. Intriguingly, we found increase in MHCII+/Siglec+/CD11clo lung cell population in CREBΔMye lungs suggesting loss of CREB in myeloid cells led to generation of incompetent pre‐AM/interstitial phenotype. Bone marrow derived macrophages from floxed and CREB lacking mice indicated dysregulation of several glycolytic enzymes, including hexokinase and pyruvate dehydrogenase. Further studies are being carried out to fully characterize the transcriptome of CREB lacking lung macrophages and whether CREB regulation of metabolic reprogramming is required for full differentiation of Pre‐AM/interstitial macrophages into AMs.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dishevelled has YAP nuclear export function in a tumour suppressor context dependent manner
Authors: Kang Hee Eun , Lee Yoonmi 
Published: June 2021

The Hippo signaling is an evolutionary conserved pathway that inhibits cell proliferation by contact inhibition, and whose loss leads to organ growth and cancer development. The Yes‐associated protein (YAP) transcription co‐activator is a key regulator of the Hippo pathway. Phosphorylation‐dependent YAP translocation is a well‐known intracellular mechanism of the Hippo pathway, however the responsible molecular effectors by which the YAP leads cytosolic translocation remain undefined. Recent findings indicate that oncogenic YAP paradoxically suppresses canonical Wnt activity.We found that DVL, a scaffolding protein of the Wnt pathway as well as a key regulator of Wnt‐independent epithelial polarity, is a molecular effector for nuclear‐cytoplasmic shuttling of YAP in a YAP‐phosphorylation dependent manner. Mutational inactivation of the nuclear export signal in DVL leads to nuclear YAP retention, with increases TEAD transcriptional activity. DVL is also required for YAP intracellular dynamics induced by E‐cadherin, α‐catenin, or AMPK activation. Importantly, the nuclear‐cytoplasmic trafficking is largely dependent on the p53‐Lats2 or LKB1‐AMPK tumor suppressor axes, which determine YAP phosphorylation status. Conversely, loss of p53 or LKB1 relieves DVL‐linked reciprocal inhibition between the canonical Wnt pathway and nuclear YAP activity. Our observations provide novel mechanistic insights into controlled proliferation coupled with epithelial polarity during development and human cancer.Support or Funding InformationNFR‐2017R1A2B3002241 funded by the Korean government (MSIP) andBK 21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inhibitory action of cTPx II on respiratory growth of yeast as a possible physiological function
Authors: Cha Mee‐Kyung , Kim Kyu‐Jung , Hong Seung‐Keun , Oh Young‐Mee , Kim Il‐Han 
Published: June 2021

A new type of peroxidase (“thiol peroxidase”; TPx) having cysteine as the primary site of catalysis has been discovered from prokaryotes to eukaryotes. Five TPx homologues were identified in Saccharomyces cerevisiae. Previously, we found that cTPx II, one of cytoplasmic form of yeast TPx isoenzymes, was highly expressed in the ΔRas2 mutant cells compared to their wild‐typed cells (YPK9) and that its expression is under negative control of Ras2 signaling. In this communication, we reported that Ras2‐delected yeast (ΔRas2 mutant) shows a growth deficiency in a non‐fermentable YPGE media as previously reported. The double mutant cell lacking both Ras2 and cTPx II (ΔRas2/ΔcTPx II) was restored to its respiratory growth. The cTPx II gene was able significantly to complement the double mutant phenotype when cTPx II was introduced into the mutant by transformation. The complementation of the ΔRas2/ΔcTPx II mutant phenotype by cTPx II gene provides the genetic evidence that cTPx II is related to the inability of respiratory growth of ΔRas2 mutant. Taken together, we, for the first time, suggest an inhibitory action of cTPx II on respiratory growth of yeast under negative control of Ras2 signaling pathway.Support or Funding InformationThis work was financially supported by NRF (2015R1D1A3A01018288).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
ABCD: The Language of Replication Protein A (RPA)
Authors: Schuld Molly , Perez Jose , Anderson C. , Bhatia R. , Ehlers M. , Leger K. , Lentz H. , Marsh S. , Haralson B. , Puls A. , Sheikh S. , Smith A. , Spellecy M. , Sweeney M. , Ya A. , Antony Edwin 
Published: June 2021

RPA is a ssDNA binding protein whose function is essential to DNA replication, recombination, and repair. RPA coordinates DNA repair processes responsible for maintaining genomic integrity, and hence is an attractive target for oncology. RPA interacts with ssDNA, and recruits other proteins onto ssDNA. RPA binds to ssDNA very tightly. Current research focuses on determining how an ssDNA‐RPA complex is removed from the DNA by weaker DNA binding enzymes. Structurally, RPA is a heterotrimer made up of three subunits (RPA70, RPA32 and RPA14). The DNA binding function of RPA is carried out by four distinct DNA binding domains (DBDs), A (residues 182 – 305), B (residues 306 – 424), C (residues 425 – 623) and D (residues 46 – 175), that directly attach to the single stranded DNA (ssDNA). DBDs A, B and C reside in the RPA70 subunit and are connected by flexible linkers. DBD‐D resides in the RPA32 subunit. The heterotrimer is held together as a complex through interactions between DBD‐C (RPA70), DBD‐D (RPA32) and the RPA14 subunit. Scientists use unnatural amino acids and chemical fluorophores to capture how each DBD binds and disconnects from ssDNA. This approach shows that DBD‐A binds rapidly to ssDNA, but detaches quickly, while DBD‐D binds more slowly to ssDNA, but is stable. Ronald Reagan High School's SMART (Students Modeling A Research Topic) Team has designed a model of RPA using 3D printing technology to investigate its structure and function. Additional research on RPA structure and mutations may prove helpful in determining cause and risk for cancer and developing potential treatments.Support or Funding InformationThe MSOE Center for BioMolecular Modeling would like to acknowledge and thank the National Institutes of Health Science Education Partnership Award (NIH‐SEPA 1R25OD010505‐01) and the National Institutes of Health Clinical and Translational Science Award (NIH‐CTSA UL1RR031973) for their support in funding the 2017–2018 SMART Team program.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.