bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Activity of LHx2‐Associated cis Regulatory Modules
Authors: Mulder Cassidy G , Watson Billy A. , Pira Charmaine U. , Shin Alexandra , Oberg Kerby C. 
Published: June 2021

Limb outgrowth is controlled, in part, by fibroblast growth factor (FGF) and sonic hedgehog (Shh). FGF up‐regulation of SHH is essential for coordinated limb pattering; however, not much is known about this mechanism. We recently found that LHX2 is an intermediate in FGF‐mediated SHH up‐regulation. LHX2 is part of a family of genes that are known to integrate signaling events. Thus, we hypothesized that FGF would up‐regulate LHX2 through associated potential cis regulatory modules (PCRM). Multiple PCRMs were found in association with the LHX2 locus. PCRMs were screened using comparative genomics, proximity to the LHX2 promoter, and transcription factor binding sites related to FGF signaling. To exam the role of suspected PCRMs, we electroporated PCRM‐reporter constructs into chick embryos. We found one PCRM with activity in the brain coincident with LHX2 expression, but none of our initial PCRMs exhibited activity in the limbs. We reevaluated the LHX2‐associated PCRMs in light of limb‐specific chromatin activation marks and identified 5 additional PCRMs for analysis. Studies are underway to determine limb‐related PCRM activity of this new cohort. Investigations regarding the relationship between FGF and LHX2 will provide important insights into the mechanisms underlying the FGF‐SHH regulatory loop.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Differences in the Serum's Metabolomics in Patients with High Plasma Atherogenic Index and Healthy Controls. Preliminary Results
Authors: Gordillo‐Moscoso Antonio , Almendra‐Pegueros Rafael , Valencia Liliana , Esmer‐Sánchez David , Florez‐Ramírez Rogelio , Rodrigez‐Aguilar Maribel , Correa‐González Jose Antonio , Tejerina Teresa , Pierdant‐Perez Mauricio , Medina Ursula 
Published: June 2021

Obesity is ones of the majors public health problems around the world, according to the World Health Organization, there were 1.9 billions adults with overweight or obesity. As we know, weight gain is associated with an increase in cardiovascular risk. The Atherogenic Index of Plasma (AIP) is the log transformation of the ratio form triglycerides between HDL cholesterol in serum. This ratio is a good measurement for the cardiovascular risk, when result >0.5 the risk for cardiovascular diseases is high. Until now metabolomics is a good tool to identify previous risk to any diseases, like gastrointestinal, immunological and cardiovascular. The aim was to compare the serum's metabolomics in patients with high plasma atherogenic index and healthy controls. We designed a case‐control study with the participation of 35 patients (12 cases and 23 controls), who complete the selection criteria (both sex, 18–75 years old, and without other diseases) and signed informed consent duly explained approved by the ethics committee. We collected anthropometric data as: weight, height and body composition; and biochemical data: HDL, LDL, total cholesterol, and triglycerides, for the calculation of AIP. For establish the differences in the serum's metabolomics and identify the most important variables of the group we did a Principal Component Analysis (PCA), random forest and Partial Least Squares (PLS) in R statics software. Results and Conclusion: The cases showed more waist circumference, triglycerides, HDL, total cholesterol, and IAP, these differences were statistically significant. (Table 1). We identify 5 principal components (56.3% variance explicated) the more representative metabolites in the cases were: 1‐Hexane,3–4 dimethyl and Heptane,2,3, dimethyl. For the controls, Cyclopentane methyl and 2H‐Pyran, Tetrahydro, more studies are necessaries for confirms these findings.Support or Funding InformationThe authors acknowledge grants from National Council for Science and Technology—National Problems (# 2015‐1340) and Infrastructure‐CONACYT (#2015‐253004).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Iron supplementation modulates genes involved in oxidoreductase activity, including prostaglandin‐endoperoxide synthase 2 in intestinal tumors
Authors: Swain James , Li Chunbiao , Leahy Patrick 
Published: June 2021

To determine the effect of excess dietary iron on gene expression of intestinal tumors in an animal model of human familial adenomatous polyposis, male C57BL/6J ApcMin/+ mice were fed adequate and excess amounts of iron (ferrous sulfate: 45 vs. 450 mg iron/kg AIN‐93M[M] diet). After 10 wk, mice were sacrificed and intestines removed. Tumors and adjacent non‐tumor tissue were excised and RNA isolated for micro‐array analysis (n=3/group; Mouse Genome 430A 2.0 arrays; Affymetrix) and RT‐PCR. Pathway mapping was performed to reveal gene networks (Pathway Studio 4.0, Ariadne Genomics, Inc.; GeneSpring, Agilent, Inc.; Searcher, Lucidyx). Bayesian ANOVA was used for micro‐arrays. Data show that intestinal tumors alter expression of a group of genes involved in oxidoreductase activity when exposed to excess iron. Differentially expressed genes include prostaglandin‐endoperoxide synthase 2, retinol saturase, alcohol dehydrogenase, deiodinase, cytochrome P450 (family 2, 4), and glutathione peroxidase. Findings reveal that iron supplementation modulates oxidoreductase activity of intestinal tumors, possibly in response to the pro‐oxidative, pro‐inflammatory effects of excess intraluminal iron.Support or Funding InformationSupported in part by grants IRG‐91‐022 from ACS (to JS) and P30CA43703 from NIH. Ferrous sulfate provided by Crown Technologies, Inc.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The effect of congenic myostatin inhibition on a mouse model of osteogenesis imperfecta (OI) type I/IV
Authors: Aguillard Ashley Michelle , Gremminger Victoria L , Daghlas Salah A , Jeong Youngjae , Lenz Kristin L , Phillips Charlotte L 
Published: June 2021

Bone is a dynamic organ in part due to its mechanosensitivity. Muscle mass and force are some of the largest physiological loads that bone experience during its life time, with muscle mass being directly proportional to bone mass. One of the factors regulating muscle mass is myostatin, a member of the TGF‐β superfamily, that acts as a negative regulator of muscle growth. Osteogenesis imperfecta (OI), commonly known as brittle bone disease, is a heritable connective tissue disorder characterized by skeletal fragility. A glycine to cysteine substitution in the proα2(I) collagen chain leads to reduced bone mineral density and compromised biomechanical integrity as modeled by the heterozygous G610C (+/G610C) mouse. +/G610C mice model both the genotype and phenotype of 64 affected individuals with mild to moderate type I/IV OI in an Old Order Amish kindred. We investigated the effects of myostatin deficiency on the +/G610C mouse muscle by breeding heterozygote myostatin deficient mice (+/mstn) with +/G610C mice to produce WT, +/mstn, +/G610C, and +/mstn +/G610C mice. After weaning at three weeks of age, mice were weighed weekly until 4 months of age when they were euthanized. After euthanization, 5 hindlimb muscles, the gastrocnemius, quadriceps, tibalis anterior, plantaris, and soleus, were harvested and weighed. Serum was separated from the blood and used to quantify myostatin levels. Serums from +/mstn and +/mstn +/G610C mice demonstrated decreased levels of myostatin as compared to WT and +/G610C mice. +/mstn mice showed increased body weights at four months of age when compared to WT littermates. +/mstn +/G610C mice also had increased body weights as compared to +/G610C littermates, although they did not reach significance. More importantly, however, +/mstn and +/mstn +/G610C mice exhibited significantly increased hindlimb skeletal muscle weights and relative muscle weights as compared to +/G610C mice for the gastrocnemius and quadriceps. These findings demonstrate that myostatin deficiency can lead to increased muscle mass in mice with OI which can potentially lead to increased bone mass and strength.Support or Funding InformationSupported by March of Dimes, National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (RO1 AR055907), the Leda J. Sears Trust, the Kansas City Area Life Sciences Institute Patton Trust Research, Inc., and the University of Missouri Research Board Grant. The project described was also supported by the IMSD EXPRESS Fellows Program (or simply the IMSD EXPRESS Program) via grant number R25GM056901 from the National Institute of General Medical Science (NIGMS), a component of the National Institutes of Health (NIH).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Impact of Transient ACE Inhibition on Cardiac Reactive Oxygen Species Enzyme Expression in Response to Nitric Oxide Synthase Inhibition
Authors: Khokar Bilal , Garvin Alexandra , Perez Octavio , Hale Taben 
Published: June 2021

We have previously shown that transient treatment with the angiotensin converting enzyme (ACE) inhibitor, enalapril, protects against future nitric oxide synthase (NOS) inhibitor, Nw‐Nitro‐L‐arginine methyl‐ester (L‐NAME)‐induced pathological cardiac remodeling. This protection is characterized by reduced inflammation, fibrosis, and collagen deposition. ACE inhibitors have been shown to reduce oxidative stress, however whether long‐term changes in pro‐ or anti‐oxidant enzymes persist after cessation of treatment is not known. The purpose of this study was to examine the expression of pro‐ and anti‐oxidative enzymes to further examine their role in the cardiac protection conferred by transient ACE inhibition. Adult male spontaneously hypertensive rats (SHR) were divided into two groups with the control group (CL) receiving vehicle and the experimental group (EL) receiving enalapril (30 mg/kg per day) for two weeks, followed by a 2‐week washout. All rats were then treated with L‐NAME for 0 or 10 days. Pro‐oxidant enzyme NOX‐2 and anti‐oxidant enzymes SOD‐1, SOD‐2 and catalase levels were determined in left ventricle via Immuno‐Blotting. Two weeks after stopping enalapril, NOX‐2 levels tended to be increased over control. In response to L‐NAME, there was a significant increase in NOX‐2 in control (CL: 115%, p<0.05), but not EL (−4%, p>0.05) hearts over baseline control levels. Catalase, SOD‐1, and SOD‐2 levels were not persistently altered by transient ACE inhibition, nor were they affected by L‐NAME in either group. Taken together, the previously‐described long‐term protection afforded by transient ACE inhibition is not due to sustained up‐regulation of anti‐oxidant enzymes. Future studies will determine whether the lack of increase in NOX‐2 levels in the hearts of EL rats is a cause or consequence of the reduced fibrosis and inflammation.Support or Funding InformationSpringboard Grant, UA College of Medicine – PhoenixThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ganglioside GQ1b induces dopamine release through the activation of Pyk2
Authors: Chen Nai‐hong , Chu Shi‐feng , Zhang Zhao , Wang Zhen‐zhen 
Published: June 2021

Growing evidence indicates that GQ1b, one of the gangliosides members, contributes to synaptic transmission and synapse formation. Previous studies have shown that GQ1b could enhance depolarization induced neurotransmitter release, while the role of GQ1b in asynchronous release is still largely unknown. Here in our result, we found low concentration of GQ1b, but not GT1b or GD1b (which were generated from GQ1b by plasma membrane‐associated sialidases), evoked asynchronous dopamine (DA) release from both clonal rat pheochromocytoma PC12 cells and rat striatal slices significantly. The release peaked at 2 min after GQ1b exposure, and lasted for more than 6 min. This effect was caused by the enhancement of intracellular Ca(2+) and the activation of Pyk2. Inhibition of Pyk2 by PF‐431396 (a dual inhibitor of Pyk2 and FAK) or Pyk2 siRNA abolished DA release induced by GQ1b. Moreover, Pyk2 Y402, but not other tyrosine site, was phosphorylated at the peaking time. The mutant of Pyk2 Y402 (Pyk2‐Y402F) was built to confirm the essential role of Y402 activation. Further studies revealed that activated Pyk2 stimulated ERK1/2 and p‐38, while only the ERK1/2 activation was indispensable for GQ1b induced DA release, which interacted with Synapsin I directly and led to its phosphorylation, then depolymerization of F‐actin, thus contributed to DA release. In conclusion, low concentration of GQ1b is able to enhance asynchronous DA release through Pyk2/ERK/Synapsin I/actin pathway. Our findings provide new insights into the role of GQ1b in neuronal communication, and implicate the potential application of GQ1b in neurological disorders.Support or Funding InformationThis work was supported by the National Natural Science Foundation of China (81730096, U1402221), CAMS Innovation Fund for Medical Sciences (CIFMS) ( 2016‐I2M‐1‐004), the Scientific Research Foundation of the Higher Education Institutions of Hunan Province (15K091), Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (BZ0150), PUMC Graduate Education and Teaching Reform Project (10023201600801).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Traditional Herbal Formula, CA01, in Mice suppresses Lung Inflammation induced by Cigarette Smoke
Authors: Park Eunsook , Jeon Woo‐Young , Seo Chang‐Seob , Ha Hyekyung , Jin Seong Eun , Kim Jinhee 
Published: June 2021

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that is characterized by abnormal inflammatory responses. CA01 has been used widely as a traditional herbal medicine for the treatment of gastrointestinal symptoms in Korea, Japan and China. In this study, we examined the therapeutic effects of CA01 on the airway inflammatory response using mice model of cigarette smoke exposure together with lipopolysaccharide (LPS) treatment. During 4 weeks, mice were exposed to cigarette smoke for 1 h on 5 days per week and instilled intranasally with LPS after smoke exposure twice. CA01 was administered by oral gavage to mice on the same 5 days. In bronchoalveolar lavage fluid (BALF), CA01 administered groups significantly decreased the numbers of inflammatory cells and production of cytokines compared with cigarette smoke combined with LPS exposed groups. Furthermore, CA01 administration reduced histologically the infiltration of inflammatory cells into lung tissues and lung fibrosis. Our data suggest that CA01 exhibits anti‐inflammatory activity against cigarette smoke combined with LPS‐induced lung inflammation. Therefore, CA01 might be a potential drug for the treatment of lung inflammatory disease such as COPD.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Phoenix dactylifera leaf extract protects from paracitamol‐induced oxidative stress in rats
Authors: Salem Gamal A , Shaban Ahmed , Diab Hussain , Elsaghayer Wesam , Mjedib Manal , Hnesh Aomassad , Sahu Ravi P 
Published: June 2021

ObjectivesTo determine the effects of leaf extract of Phoenix dactylifera against the oxidative stress response induced by a wide‐spectrum analgesic paracetamol in rats.MethodsAdult Sprague dawley rats were treated with or without paracetamol (1500mg/kg) and leaf extract of Phoenix dactylifera (300mg/kg). Serum samples were collected to evaluate liver function tests, and hepatic tissue samples were obtained to assess oxidative stress‐related markers and histopathological examination.ResultsPhoenix dactylifera ameliorated paracetamol‐induced elevated serum liver markers such as alkaline phosphatase (ALP), aminotransferases (AST), alanine aminotransferase (ALT) and bilirubin. In addition, Phoenix dactylifera restored paracetamol‐induced reduced levels of liver tissue antioxidant enzymes such as glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Histological analysis demonstrate that Phoenix dactylifera conserved the hepatic tissue against lesions such as inflammation, centrilobular necrosis, and hemorrhages induced by PCM.ConclusionThese findings indicate that Phoenix dactylifera possesses protective effects against paracetamol‐induced liver injury and oxidative stress, and could be used to explore against drug induced deleterious effects in experimental models.Support or Funding InformationNo funding supportThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Experimentally‐Driven Molecular Docking via a Hybrid Approach
Authors: Roberts Arthur 
Published: June 2021

High Ambiguity‐Driven biomolecular DOCKing (HADDOCK) protocols with CNS/Xplor and AutoDock Vina are powerful tools for drug receptor docking. AutoDock Vina performs blind drug docking and virtual drug screening very efficiently. Unfortunately, in many cases, the bound drug conformations determined by AutoDock Vina does not necessarily correlate well to experiments. On the other hand, docked conformations by HADDOCK are driven by experimental data combined with molecular dynamics, so they tend to correlate more to the experimental data. Unfortunately, this approach is considerably less efficient than AutoDock Vina and small molecules can become trapped in local energy wells during initial stages of docking. As a result, a seamless Python wrapper called HADDOCK‐Vina combining AutoDock Vina, CNS/Xplor, HADDOCK, MSMS, OpenBabel, ProPKA, Reduce and Volume Assessor together in a single package was developed. The experimental data is inputted in a simplified format with a few lines in HADDOCK‐Vina and produces a distance restraint file to be used in CNS/Xplor that has thousands of lines. The receptor is automatically processed and protonated by ProPKA within the wrapper. The HADDOCK‐Vina automatically produces and AutoDock search box over the entire receptor and a customized version AutoDockVina completely covers the surface of the receptor with ligand molecules. These bound ligands are filtered using the experimentally‐derived distance restraints and the experimentally‐related scoring algorithm of HADDOCK called the HADDOCK score (Hscore). By default, the three bound ligands with the lowest Hscore and the lowest energy are automatically refined further by energy minimization and simulated annealing using the HADDOCK protocols within CNS/Xplor. In this work, to demonstrate the effectiveness of the software, we show that we can reproduce ligand‐bound X‐ray protein crystal structures using only experimentally‐derived distance restraints. We also compare the wrapper to the individual software programs.Support or Funding InformationThis work is supported by NIGMS NIH R15 (R15GM107913‐01A1) and NCI NIH R01 (R01CA204846‐01A1) grants.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Confounding effect of UGT1A1 interindividual variability on inhibition of its in vitro activity by kinase inhibitors.
Authors: Alade Nathan , Basit Abdul , Zhang Haeyoung , Bhatt Deepak , Collins Carol , Prasad Bhagwat 
Published: June 2021

Background and ObjectiveInhibition of UGT1A1 by kinase inhibitors (KIs) has been shown to cause mild to serve hyperbilirubinemia in cancer patients1. UGT1A1 is highly polymorphic and displays variable expression. The specific aims of this study were i) to stratify human liver microsomes (HLMs) based on UGT1A1 abundance, activity and genotype, ii) to screen 10 clinically used KIs for their UGT1A1 inhibition potential, and iii) to determine inhibition potential (IC50) of the top three potent KIs in high and low UGT1A1 expressing HLM samples.MethodsTargeted genotyping of liver tissue donors (N=445) was performed; and UGT1A1 protein abundance and activity in HLM samples were quantified using a validated proteomics method and using bilirubin or estradiol as probe substrates, respectively. The mono and di‐bilirubin glucuronides and estradiol 3‐β‐D‐glucuronide (E3βG) were monitored by LC‐MS/MS. Association analysis of UGT1A1 genotype with protein abundance or activity was performed. Screening of UGT1A1 inhibition by KIs (at 1 and 20 uM) was performed using a high UGT1A1 expressing (46.7 ± 4.6 pmol/mg) HLM sample. IC50 values of KIs for UGT1A1 were determined using above mentioned high and a low (10.1 ± 1.6 pmol/mg) expressing HLM samples.ResultsUGT1A1 abundance and activity exhibited age‐dependent maturation with 8‐fold increase from neonates to adults. UGT1A1 SNPs rs10929302, rs887829, rs111741722 and rs4124874, are associated with decreased UGT1A1 abundance and activity, whereas rs8175347 was only associated with decreased abundance. Glucuronidation of both substrates was inhibited by the KIs in a substrate‐independent manner in the following order (% inhibition of E3βG activity at 1 and 20 μM in parenthesis): dasatanib (46 and 91)> sorafenib (11 and 74)> temsirolimus (50 and 71)> sirolimus (0 and 63) > sunitinib (21 and 38) > nilotinib (22 and 34) > gefitinib (0 and 29) > pazopanib = imatinib = lapatinib (0). The top three KIs showed differential IC50 values for E3βG inhibition in high and low UGT1A1 expressers, i.e., dasatanib (2.0, and 4.0), sirolimus (IC50= 7.6, and 32.6), and sorafenib (0.95, and 18.0), respectively.DiscussionUGT1A1 abundance is highly variable with significant effect of age and genotype. Inter‐individual variability in UGT1A1 plays a confounding role in predicting drug‐endobiotic or drug‐drug interactions (DDIs) mediated by this enzyme. Identification of genetic or non‐genetic factors associated with UGT1A1 activity will allow better prediction of UGT1A1 mediated drug metabolism and toxicity.Support or Funding InformationThis work was primarily supported by the National Institutes of Health [Grant no. R01 HD081299].

NA and AB contributed equally to this work.
This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.