bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mogat1 is a fasting‐induced PPARα target gene that plays a role in coordinating the hepatic response to food deprivation
Authors: Lutkewitte Andrew John , McCommis Kyle S. , Chambers Kari T. , Graham Mark J. , Hall Angela M. , Finck Brian N. 
Published: June 2021

During prolonged fasting, the liver plays a central role in maintaining systemic energy homeostasis by producing glucose and ketones in processes fueled by oxidation of fatty acids liberated from adipose tissue. In mice, this is also accompanied by transient hepatic accumulation of complex lipids in the form of triglycerides. In mice fasted for 24 hours, the hepatic expression of Mogat1 was significantly increased compared to mice given ad libitum access to food. Mogat1 encodes an enzyme with monoacylglycerol (MAG) acyltransferase (MGAT) activity, which is an understudied step in glycerolipid synthesis. Basal and fasting‐induced expression of Mogat1 was markedly diminished in liver of mice lacking the transcription factor peroxisome proliferator‐activated receptor α (PPARα). Suppressing Mogat1 expression with antisense‐oligonucleotides (ASO) reduced hepatic MGAT activity and hepatic triglyceride content compared to fasted ASO control treated mice. Surprisingly, the expression of many other known PPARα target genes (Dgat1, Mgll, Cpt1α, Acadm, and Acadl) was also decreased in mice treated with Mogat1 ASO. We postulated that inhibiting Mogat1 suppressed PPARα activity, potentially by loss of a ligand for PPARα. Fasted mice treated with control or Mogat1 ASO were gavaged with the synthetic PPARα ligand WY‐14643, which reversed the effects of Mogat1 ASO on liver triglyceride content as well as PPARα target gene expression. In conclusion, Mogat1 is a fasting‐induced PPARα target gene and MGAT and may feed forward to regulate liver PPARα activity during fasting.Support or Funding InformationA.J.L. was supported by funds from NIH training grant T32 DK07120. K.S.M is supported by K99 HL136658 and A.M.H. is supported by 17‐IBS‐109 from the American Diabetes Association and R56 DK111735. This work was also funded by R01 DK078187 to B.N.F. The Core services of the Diabetes Research Center (P30 DK020579) and the Nutrition Obesity Research Center (P30 DK56341) at the Washington University School of Medicine also supported 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.
Effect of Elevated ω‐3/ω‐6 PUFA ratio on High‐Fat Diet and Acute Ethanol‐induced Obesity, Glucose Intolerance and Liver Injury in Mice
Authors: Dastidar Shubha Gosh , Warner Dennis , Song Ying , Warner Jeffrey , McClain Craig , Kirpich Irina 
Published: June 2021

Rationale and ObjectivesNonalcoholic and alcoholic fatty liver disease (ALD and NAFLD) are both serious health and socioeconomic problems worldwide, with similar pathological spectra, ranging from simple hepatic steatosis to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. ALD and NAFLD have also several similar risk factors, including certain dietary factors and obesity. Human and animal studies have demonstrated that a Western diet, rich in ω‐6 polyunsaturated fatty acids (PUFAs) and low in ω‐3 PUFAs, exacerbates NAFLD and ALD. In addition, obese alcohol drinkers might be at an increased risk of developing more severe liver injury. The objective of the present study was to investigate whether a decrease in ω6 PUFAs with subsequent increase in the ω‐3/ω‐6 PUFA ratio ameliorates metabolic derangements and liver injury in a two‐hit model of long‐term HFD feeding plus a single EtOH binge administration.MethodsFemale fat‐1+/− (mice with the ability to endogenously convert ω6 to ω3 PUFA) and WT littermates were fed low or high fat diets (LFD and HFD, 10% and 60%, respectively) for 12 weeks. On the last day of the experiment, mice received a single dose of EtOH (5 g/kg) by oral gavage. Animals were euthanized 9h‐post gavage. Metabolic parameters and liver injury were evaluated.ResultsLong‐term HFD feeding resulted in alterations of metabolic parameters in both genotypes. However, compared to WT, fat‐1+/− gained significantly less body weight (BW), and had less parametrial fat at the end of the study. This could be due to significantly lower food consumption in fat‐1+/− mice. Liver weight/BW ratio was equally reduced in HFD‐fed mice compared to LFD. While the type of the diet did not affect the pancreas weight/BW ratio, ethanol administration resulted in an opposite effect on this parameter in WT (increase) and fat1−/+ mice (decrease). Analysis of liver injury revealed that HFD led to similar induction of ALT levels (a marker of liver injury) in both genotypes, which was further equally elevated by ethanol administration. However, ethanol challenge resulted in significant increase in ALT levels in LFD fed mice in WT but not fat1−/+ littermates.ConclusionsIncrease in endogenous ω‐3/ω‐6 PUFA ratio was not beneficial against HFD and binge EtOH‐induced liver damage (two‐hit model), however, mice fed a LFD were protected against EtOH‐mediated liver injury. The molecular mechanisms underlying these effects needs to be further investigated.Support or Funding InformationSupported by grants from NIH and Veterans AdministrationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Targeting molecular chaperone HSP90 to treat Niemann‐Pick type C1 disease
Authors: Pipalia Nina H. , Maxfield Frederick R. 
Published: June 2021

NPC1 is a fatal, lysosomal neurovisceral storage disease caused by mutations in the npc1 gene. More than 200 different disease‐associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids and other lipids in late endosome/ lysosomes (LE/Ly) of many cell types. There is no FDA‐approved therapy to treat NPC1 disease. A limited initial human trial of hydroxyl propyl cyclodextrin (HPCD) is currently in progress, but HPCD does not cross the BBB. Based on our previous findings on NPC1I1061T skin fibroblast, a small clinical trial is also in progress on the treatment of histone deacetylase inhibitor (HDACi), Vorinostat. Our data suggested that HDACi treatment on skin fibroblasts results in increased expression of the Niemann‐Pick type C1 (NPC1) protein in mutant cells. Using an engineered human cell line, we have also observed that HDACis, can correct the NPC1 cholesterol storage defect in 60 of the 81 NPC1 mutants tested. Although significant progress has been made in understanding the pathology of NPC1 disease, the mechanisms governing the proteostatic control of NPC1 protein is not completely understood. However, being an epigenetic modifier, HDACi is known to alter the pattern of gene expression. As a result, off‐target effects are of a major concern in using HDACi's as a therapy. In order to understand the molecular mechanism of HDACi on NPC1, we considered potential cellular targets of HDACi other than histones. Disruption of molecular chaperone HSP90 (via hyperacetylation) is one of the many consequences of HDACi treatment.We, therefore, evaluated the effect of direct inhibition of HSP90 family of proteins on NPC1 skin fibroblasts in terms of lowering lysosomal cholesterol accumulation. Our results indicated that out of the three HSP90 family proteins, selectively HSP90A and not HSP90B or TRAP inhibition resulted in clearance of cholesterol from lysosomes as well as aided in mobilizing unfolded mutant NPC1 protein from ER to lysosomes. Hence the data on the effect of several different HSP90 inhibitors on multiple human patient‐derived skin fibroblast in lowering lysosomal cholesterol burden using microscopy based filipin assay will be presented. Our previous published work using HDACi and recent preliminary results using heat shock protein HSP90 inhibitors suggests that cytosolic HSP90 and associated chaperones may be a target and indicates that protein folding quality control plays a critical role in NPC1 diseases. An attempt will be made to elucidate the role of cytosolic HSP90 and its associated co‐chaperones in the regulation of NPC1 mutant protein stability.Support or Funding InformationAra Parseghian Medical Research FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Protein Expression from Measles (MV) L Protein Genes Optimized and Suboptimized to Human and Canine Codon Usage Bias Varies with Construct and Cell Type
Authors: Shah Akash , Uhl Elizabeth W. , Osborn Michelle L. , Michel Frank , Hogan Robert J. 
Published: June 2021

The purpose of this study was to characterize protein expression from constructs of the MV polymerase (L) gene optimized to human and canine codon usage bias (CUB). All codon changes made were synonymous in that the amino acid coded for was unchanged. Four constructs of the MV L gene were transfected into human (HEK 293) and canine (A‐72) cells: 1) human CUB optimized, 2) canine CUB optimized, 3) human CUB sub‐optimized, and 4) wild type (WT). Protein expression from transfected cells was assessed using fluorescent labeling and Cellomic analysis. Human cells transfected with constructs of the MV L gene optimized to human or canine CUB had increased expression compared to cells containing WT or sub‐optimized constructs. In contrast there was no difference in the levels of protein expression in canine cells transfected with the MV L gene constructs. These results complete analysis of the effects of human and canine CUB optimization on protein expression from MV genes. Overall these studies indicate that synonymous codon changes in viral nucleic acid sequences can alter protein expression in a variety of ways, some of which are likely to impact viral pathogenicity.Support or Funding InformationThe project depicted was sponsored by the Department of Defense Threat Reduction Agency. The content of the information does not necessarily reflect the position or the policy of the federal government, and no official endorsement should be inferred.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Environmental Enrichment Increases Alcohol Reward Via Modulation of The Oxitocinergic System
Authors: Rae Mariana , Zanos Panos , Georgiou Polymnia , Bailey Alexis , Devi Lakshmi , Camarini Rosana 
Published: June 2021

Environmental enrichment (EE; model of “eustress”) has been hypothesized to prevent and reverse drug addiction‐related behaviors. Our group has already shown a protective effect of EE on ethanol sensitization and alcohol consumption. However, the mechanisms underlying these effects are not known. The aim of this study was to evaluate the effect of EE on alcohol reward. Swiss male mice (PDN=70) were distributed in control (reared in standard cages) and EE (kept in large cages with objects and a running wheel) groups, during 21 days. We first behaviorally characterized the effects of EE on alcohol (2.0 g/Kg, i.p) conditioned‐place preference (CPP). Since one of the main pillars of EE is increased social interaction, we accessed the effects of EE on the OT peptide and OT receptor (OTR), via ELISA and autoradiography, respectively. Although all mice showed ethanol CPP, EE group exhibited higher ethanol preference, suggesting a sensitization of the reward system induced by EE. EE animals had higher OT levels in the hypothalamus and lower OTR binding in the olfactory nuclei, frontal and piriform cortices, brains regions involved in social information processing. Taken together, these results indicate that EE can modulate the OT system by increasing OT synthesis in the brain, leading to OTR downregulation in specific brain regions. To assess the functional role of the OT neurotransmission in the observed EE‐induced enhancement of ethanol CPP, we studied the effects the OT analogue, carbetocin (CBT) (6.4 mg/kg/day, i.p) and the OTR antagonist, L,369–899 (OTR‐A) (5 mg/kg/day, i.p) in that paradigm. CBT administration, similar to EE, enhanced alcohol CPP in control animals. Conversely, treatment with the OTR‐A during the EE exposure blocked this enhancement in ethanol CPP. These findings suggest that EE enhances ethanol rewarding effects via a direct modulation of the OT system. In conclusion, we demonstrated that EE and OT treatment may constitute a risk factor that may predispose to alcohol use. Therefore, OT‐based therapies regarding alcohol addiction should be considered cautiously, particularly in the early stages of alcohol use.All the animal studies were conducted in accordance with Ethical Committee for Animal Use (CEUA) of the University of São Paulo, registered under protocol nº 132, page 110, book 02.Support or Funding InformationSupported by CAPES, CNPq, FAPESP and SantanderThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Signal Transduction Pathway Gene Regulation by Long‐Term Treatment with CART Peptide
Authors: Ma Leon , Burgos Gabriel , Wang Xia , Prinster Steven 
Published: June 2021

The cocaine‐ and amphetamine‐regulated transcript (CART) was first isolated from rat striatum following the acute administration of cocaine or amphetamine. It was quickly determined that CART or CART peptide was expressed in a variety of tissues affecting a wide range of important processes. Although the identity of the CART receptor has not been discovered, its ability to stimulate ERK1/2 in a pertussis‐sensitive manner, and to inhibit AKT phosphorylation suggests that it is a G‐protein coupled receptor (GPCR) coupled to an inhibitory G protein. To gain further insight into the identity of the CART peptide receptor, we investigated the effects of CART peptide activation on other pathways by subjecting differentiated PC12 cells to long‐term (24 hour) incubation with CART peptide. Changes in mRNA expression were assessed using PCR arrays with cDNA probes for a variety of general signal transduction proteins or proteins involved in Gi signaling. Changes in genes related to cAMP and AKT signaling pathways as well as changes in genes for proteins involved in the ERK1/2 activation pathway were observed. Specifically, upregulation of Atf4, SLC2a1 and Map2k2 were noted. Further study of these pathways may provide additional information that will lead to the identification of the CART peptide receptor and therapeutic uses for the CART peptide.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Relaxation of Porcine Isolated Irides by Novel Hydrogen Sulfide‐Releasing Compounds
Authors: Robinson Jenaye , Mitchell‐Bush Leah , Whiteman Matthew , Opere Catherine , Ohia Sunny , Njie‐Mbye Ya Fatou 
Published: June 2021

PurposeWe have previously reported that hydrogen sulfide (H2S)‐releasing compounds can elicit relaxation of pre‐contracted ocular vascular and non‐vascular smooth muscles. In the present study, we compared the pharmacological actions of novel mitochondrial‐targeting H2S‐releasing compounds (AP39, AP123, and RT‐01) with those of ADT‐OH on pre‐contracted porcine isolated irides.MethodsIsolated porcine iris muscle strips were set up in organ baths containing oxygenated Krebs buffer solution maintained at 37° C and gassed with 95% O2 and 5% CO2. The muscle strips were set to an initial resting tension of 0.15 g and longitudinal isometric tension was recorded via a grass FT03 Force‐Displacement Transducers and analyzed using the PolyView computer software. Pharmacological actions of AP39, AP123 and RT‐01 were assessed in the presence of tone induced by submaximal concentrations of the muscarinic agonist, carbachol. The cyclo‐oxygenase inhibitor, flurbiprofen (10 μM) was added to Krebs buffer solution during the incubation period and was present for duration of the experiments. ADT‐OH was used as a positive control in experiments using AP39, AP123 and RT‐01 since it lacked the mitochondrial targeting moiety.ResultsAP39 (1 nM – 10 μM), RT‐01 (1 nM – 10 μM) and AP123 (1 nM – 10 μM) elicited concentration‐dependent relaxations of carbachol‐induced tone. The rank order of activity was as follows (IC50): AP39, 50 nM (n = 10); RT‐01, 100 nM (n = 4); and AP123, 300 nM (n = 4). Likewise, the non‐mitochondrial‐targeting H2S donor, ADT‐OH (1 nM – 10 μM) caused a concentration‐dependent relaxation of porcine irides with an IC50 of 50 nM (n = 8).ConclusionsWe conclude that both novel mitochondria‐targeting H2S‐releasing compounds and their control counterpart, ADT‐OH can elicit relaxation of isolated porcine irides. The mitochondrial storage sites of this gas may not be involved in the inhibitory response caused by H2S‐releasing compounds in the porcine iris smooth muscle.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of Omega‐3 Fatty Acid Supplementation on Resolvin (RvE1)‐mediated Suppression of Inflammation in a Mouse Model of Asthma
Authors: Siddiquee Armaan , Patel Mehaben , Rajalingam Sahith , Kurade Mangesh , Narke Deven , Ponnoth Dovenia S. 
Published: June 2021

ResolvinE1(RvE1), an endogenous lipid mediator derived from eicosapentaenoic acid (omega 3 fatty acids), contributes to the resolution of an allergic inflammatory response. We investigated the effects of RvE1 and Omega 3 fatty acids in airway reactivity and inflammation using an asthmatic murine model. Mice were divided into control (CON) and allergen sensitized‐challenged (SEN) groups, and were sensitized i.p. on days 1, 6 with 20μg ovalbumin (OVA) followed by 5% OVA aerosol challenges on days 11–13. RvE1 was administered intraperitoneally post‐allergen challenge while fish oil was administered via oral gavage once daily (day 1 through 13). Whole body plethysmography (measuring airway responsiveness as enhanced pause, Penh) and bronchoalveolar lavage (BAL) studies were performed. RvE1attenuated airway responsiveness to methacholine (MCh; 48mg/ml) in treated mice (150±27.88% in SEN vs. 54±7.52% in SEN+RvE1, p<0.05). However, no difference was observed with either omega‐3 supplementation alone (115±19.28%in SEN+omega‐3) or additive effect of omega‐3 on RvE1 treatment (39±12.37% in SEN+RvE1+omega‐3 vs. 54±7.52% in SEN+RvE1). Differential BAL cell analysis showed that post‐treatment with RVE1 decreased eosinophils (40 ± 2.7% in SEN vs.10.2 ± 1.4% in SEN+RvE1, p<0.005). Omega‐3 treated SEN showed no difference (45 ± 3%) while SEN+RvE1+omega‐3 group had similar results as RvE1 treated mice (10.2 ± 1.4% in SEN+RvE1 vs.10.6 ± 1.4% in SEN+RvE1+omega‐3), suggesting that RvE1 only attenuated the eosinophilia. Our data suggests that omega‐3 supplementation has little effect on airway inflammation and reactivity. Further, omega‐3 fatty acid, although a precursor for resolvin formation, did not have additive effects on resolvin‐mediated decreases in airway inflammation and airway reactivity.Support or Funding InformationLong Island University start‐up funds (DSP)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Vinca Alkaloid Pharmacokinetics in the Context of a Physiologically‐Based Murine Model
Authors: Collins Keagan P. , Mannheimer Joshua D. , Gustafson Daniel L. 
Published: June 2021

Vinca alkaloids are a class of molecule clinically used as cytotoxic chemotherapeutics, and exert their activity through mitotic disruption by preventing the polymerization of microtubules. While successfully used to treat a variety of cancer types, patients receiving these treatments remain at risk of toxic side‐effects due to significant variability observed in drug disposition. The objective of this study was to characterize the primary factors driving vinca alkaloid pharmacokinetics (PK), and develop a model capable of predicting PK based on alterations in these drivers. Physiologic sources of variability are known to include a wide range of reported values for CYP3A‐mediated metabolism and plasma protein binding, as well as a strong correlation between tissue uptake and tissue tubulin content. Additionally, vinca alkaloids are known substrates of ABCB1 (MDR1, PGP), which mediates drug efflux from tissues. To investigate dependence on these factors we initially developed a physiologically‐based pharmacokinetic (PBPK) model for vinblastine (VBL) dosed IV at 2 mg/kg in MDR1a −/− (KO) and MDR1a +/+ (WT) mice. An increase in VBL exposure was observed in all KO tissues compared to WT, particularly in brain which accumulated roughly 10‐fold more VBL over 6 hours. This is of particular importance as neurotoxicity is the most commonly reported dose‐limiting toxicity for vinca alkaloids. Additionally, excretion through biliary and renal routes were 6‐fold and 10‐fold lower, respectively, for both VBL and the active metabolite, desacetylVBL. Using known physiological and biochemical parameters the PBPK model was developed and validated for key organs involved in distribution, metabolism, and excretion of VBL in the MDR1a WT and KO mice. Through adjustment of relevant biochemical parameters the model was validated for vincristine (VCR) PK in MDR1a WT mice receiving the same 2mg/kg IV bolus dose, and used to simulate what VCR PK might look like in an MDR1a KO scenario. The validated PBPK model for VBL and VCR allows for investigation of PK based on alterations in measurable, physiologically‐relevant driving factors in murine models. Due to the pharmacologic similarities between molecules within the vinca alkaloid class, biochemical parameters can easily be adjusted to predict PK of vindesine and vinorelbine as well. Value of this model lies in its ability predict exposure in pre‐clinical studies involving vinca alkaloids, and provide insight into how exposure would be altered in combination therapy or gene knockout settings.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.