bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fluoxetine Ameliorates the Depressive‐Like Behaviors and Metabolic Abnormalities Induced by Chronic High‐Fat Diet
Authors: Chiu Yen‐Ju , Chen Yun‐Wen 
Published: June 2021

Major depressive disorder (MDD) is one of the most common psychiatric disorders, and frequently co‐occurs with multiple comorbidities, especially Type 2 diabetes mellitus. Selective serotonin reuptake inhibitors (SSRIs) are the most widely used class of antidepressants. This study aimed to investigate the effects of fluoxetine (Prozac®), a SSRIs, on metabolic abnormalities induced by chronic high‐fat diet (HDF). Male HDF‐induced insulin resistance mice were administrated with fluoxetine (10 mg/kg and 20 mg/kg) by intraperitoneal injection for four weeks. The behavioral tests showed that fluoxetine significantly reversed the depressive‐like behaviors induced by chronic HDF, including the reduced sucrose preference and increased immobility time in the forced swimming test and tail suspension test. Moreover, fluoxetine also reduced serum level of glucose and improved blood lipid profiles in HFD‐treated mice. Furthermore, fluoxetine improved impaired glucose tolerance and insulin sensitivity. Our results indicated that fluoxetine could ameliorate depressive‐like behaviors and metabolic abnormalities induced by chronic HFD, which suggested that the multiple effects of fluoxetine could be beneficial for patients with depression and/or metabolic syndrome.Support or Funding InformationThis work is supported by Ministry of Science and Technology, Taiwan (MOST 106‐2320‐B‐006‐058‐MY3)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Novel Animal Model to Investigate the Pathophysiology of Atherosclerosis Through Regulation of Cholesterol Homeostasis and the Highly Atherogenic LDL‐L5
Authors: Chang Christopher , Yang Tzu‐Ching , Lu Shao‐Chun , Chang Po‐Yuan 
Published: June 2021

The electronegative low‐density lipoprotein (LDL) L5 is elevated in hypercholesterolemic plasma and can induce apoptosis in coronary endothelial cells. The atherogenic potential of L5 renders it an important therapeutic target for cardiovascular disease but the exact mechanisms how plasma L5 concentrations can be regulated by cholesterol intake remains unclear. In this study, we developed an animal model to investigate the inducibility of plasma L5 by cholesterol and test the LDL‐lowering effect of ezetimibe, an inhibitor of intestinal cholesterol absorption, in male Golden Syrian hamsters. The hamsters were fed diets containing high fat and 1% cholesterol (HFC diet) for 2 weeks and LDLs were purified from hamster plasma by ultracentrifugation followed by ion exchange liquid chromatography. The eluting patterns of LDL in hamsters revealed five subfractions, named L1 to L5, which were similar to those obtained from hypercholesterolemic human plasma. HFC‐fed hamsters had highly elevated plasma L5, expressed as L5/LDL ratio, of 48.8±13.4% (n=6) compared with the hamsters fed with normal chow diet (18.9±2.7%; n=4). When the cholesterol absorption inhibitor ezetimibe was added to the HFC diets at the dose of 1mg/day/kg body weight, the plasma L5 levels were significantly reduced compared to non‐ezetimibe group (32.1±11.3% vs. 48.8±13.4%; n=6). Hamsters fed with normal chow diet also demonstrated a modest reduction of L5 with ezetimibe (14.1±11.3% vs. 18.9±2.7%; n=4). The time interval required to reduce plasma L5 by ezetimibe was only two to four weeks, consistent with the cholesterol‐lowering effect of ezetimibe in human. Therefore, we have established a novel hamster‐L5 model to investigate the pathophysiology of atherosclerosis in vivo. This animal model can also serve as a screening tool to identify LDL‐ and L5‐lowering therapy for cardiovascular disease.Support or Funding InformationThis work was supported by grants NSC101‐2320‐B‐002‐026 from the National Science Council and MOST‐106‐2314‐B‐002 ‐156 ‐MY2 (Dr. Po‐Yuan Chang) from the Ministry of Science and Technology, Taipei, Taiwan.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
RNA seq Analysis of Livers from Mice Lacking Fatty Acid Transport Protein 2 (FATP2) Demonstrate Metabolic Linkages in Genes Involved in PPARa‐responsive Lipid Metabolic Pathways
Authors: Perez Vincent , Behrens Mark , DiRusso Concetta C. , Black Paul N. 
Published: June 2021

Fatty acid transport protein 2 (FATP2) is highly expressed in liver, small intestine and kidney where it functions in both the uptake of exogenous long chain fatty acids and in the activation of very long chain fatty acids. Previous studies from this lab have found that when the fatty acid uptake is attenuated using the FATP2‐specific inhibitor Lipofermata, cells that express this protein are protected from lipotoxicity. These observations support the notion that FATP2 functions as a gate in regulating the uptake of exogenous fatty acids, which are linked to downstream lipid metabolic events. In the present study, we completed a comprehensive RNA seq analysis to address the impact of deleting FATP2 in the liver on the transcriptome. Wild type (C57BL/6NJ) and FATP null (FATP2−/−) mice (5 weeks old) were maintained on standard chow diet for 6 weeks. Over this period of time, the FATP2−/− mice had reduced weight gain and lowered blood triglyceride levels compared with control mice. A number of lipid metabolic genes in the liver were increased in the FATP2−/− mice that mapped to the gene ontology categories beta‐oxidation, peroxisome biogenesis, fatty acid trafficking and arachidonic fatty acid/eicosanoid metabolism. These metabolic systems are linked through activity of the transcription factor PPARa suggesting endogenous expression was elevated possibly through increases in a proximal ligand when FATP2 is absent. This correlated with increased expression of phospholipase A2. To address these changes further, we employed untargeted (NMR) and targeted (LC‐MS/MS) metabolomics experiments, which showed there were no major differences in the abundance of substrates in central carbon metabolism between the wild type and FATP2−/− livers, but there was a significant increase in the eicosanoids LXA4 and PGJ2 in the FATP2−/− livers. Taken together, the expression of FATP2 appears to have a broad impact on the expression of key lipid metabolic genes that may be linked through increased levels of bioactive lipid mediators.Support or Funding InformationThis work has been supported by the Agricultural Research Division of the University of Nebraska.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cross Regulation of Phospholipid and Unsaturated Fatty Acid Biosynthesis
Authors: Dible Sarah , McDonough Virginia 
Published: June 2021

Considering the requirement for unsaturated fatty acids (UFAs) to produce phospholipids, we investigated the potential cross regulation of phospholipid and UFA biosynthesis. The Δ‐9 desaturase, encoded by OLE1, is the sole source of endogenous UFAs in Saccharomyces cerevisiae. Inspection of the OLE1 promoter revealed several sequences that are close matches to the regulatory sequence, UASINO, found in many phospholipid biosynthetic genes, and is the target of regulation by Ino2p, Ino4p and Opi1p. We then examined if these proteins also play a role in regulation of OLE1 expression. Reporter gene analysis showed that when uracil prototrophy was placed under control of the OLE1 promoter, poor expression was observed in an opi1 mutant. When lacZ was placed under control of the OLE1 promoter, reporter assays confirmed that expression was poor in the opi1 mutant. Fatty acid analysis revealed that normal regulation of OLE1 occurred in response to unsaturated fatty acid (UFA) supplement in the opi1 mutant, indicating that post‐transcriptional regulation is still functional. Finally, the 2 hybrid assay was used to examine potential interactions between Opi1p and Ole1p, Ino2p, Ino4p and known OLE1 regulators Mga2p and Spt23p. While no unexpected Opi1p interactions were detected, we observed that Ino4p interacts with Mga2p in this assay. This preliminary work indicates that phospholipid regulators also play a role in regulating OLE1 expression.Support or Funding InformationWe acknowledge the support of the Hope College Biology Department, and the Hope College Dean of Natural and Applied Sciences.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Acyl‐CoA Synthetase 6 Mediates Brain Docosahexaenoic Acid (DHA) Enrichment and Neuroprotection
Authors: Fernandez Regina F , Kim Sora Q , Ellis Jessica M 
Published: June 2021

The omega‐3 fatty acid, docosahexaenoic acid (DHA), is enriched in the central nervous system and thought to protect against neurological dysfunction. Yet, studying the role of brain DHA metabolism in the development of neurological dysfunction has remained limited because the biochemical mechanisms regulating DHA enrichment in the brain remain unclear. To define a critical regulatory node in brain DHA biochemistry we targeted long chain acyl‐CoA synthetase 6 (Acsl6) because this enzyme initiates cellular fatty acid metabolism, is enriched in the brain and prefers DHA as its substrate. Genetically deleting Acsl6 in mice resulted in large and specific reductions (35–72%) in DHA‐containing phospholipids across tissues that highly express Acsl6 (i.e. the central nervous system). Acsl6−/− mice develop age‐related deleterious neurological pathology characterized by increased astrogliosis and microglia. Surprisingly, this pathology develops in the absence of alterations in pro‐ and anti‐inflammatory lipid mediators, suggesting alternative mechanisms mediating neuroinflammation in Acsl6‐induced DHA deficiency. Together our findings demonstrate a novel central nervous system DHA‐deficient model susceptible to aging‐induced neuroinflammatory pathology.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
CysLT1R regulates cys‐LT‐mediated calcium influx and oxidized LDL‐uptake in macrophages
Authors: Pokhrel Sabita , Duah Ernest , Paruchuri Sailaja , Thodeti Charles 
Published: June 2021

Cysteinyl leukotrienes (cys‐LTs), LTC4, LTD4, LTE4 are potent inflammatory lipid mediators that act through two distinct G‐protein‐coupled receptors, CysLT1R and CysLT2R. Although cys‐LTs are shown to induce vascular leakage and atherosclerosis, the molecular mechanism by which cys‐LTs modulate endothelial and macrophage functions are not well understood. Atherosclerosis is the chronic inflammatory disease that accounts for the global epidemic of cardiovascular diseases (CVD), mainly driven by endothelial dysfunction. We have recently shown that cys‐LTs regulate endothelial cell (EC) dysfunction via CysLT2R, enhancing EC contraction and permeability. Further, cys‐LTs enhance TNFα‐mediated up‐regulation of VCAM‐1 and attachment of THP‐1 cells to endothelium. Therefore, we further focused on cys‐LT‐mediated effects in Raw and THP‐1‐derived macrophages. We observed that macrophages express mainly CysLT1R and flux calcium via CysLT1R in response to LTD4. Further, LTD4 significantly promoted oxidized low density lipoprotein (ox‐LDL) uptake by macrophages. Importantly, LTD4 treatment enhanced the expression of a scavenger receptor CD36, Oxidized low‐density lipoprotein receptor 1 (OLR1), Monocyte chemoattractant protein 1 (MCP1) and Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α) transcripts suggesting that these receptors could mediate LTD4‐induced ox‐LDL uptake by macrophages contributing to atherosclerosis.Support or Funding InformationNIH R15 grant (1R15HL133918), and James Foght Professorship support.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of Cysteinyl Leukotriene 2 Receptor in Tumor Angiogenesis, Permeability and Metastasis
Authors: Teegala Lakshminarayan Reddy , Duah Ernest , Kondeti Vinay , Adapala Ravi K , Keshamouni Venkateshwar G , Kanaoka Yoshihide , Austen K Frank , Thodeti Charles K , Paruchuri Sailaja 
Published: June 2021

Cysteinyl leukotrienes (cys‐LTs) are pro‐inflammatory mediators that enhance vascular permeability through distinct receptors (CysLTRs). We found that CysLT2R regulates angiogenesis in isolated mouse endothelial cells (EC) and in Matrigel implants in WT mice, and enhances EC contraction and permeability via Rho‐dependent myosin light chain 2 and VE‐cadherin axis. Since solid tumors utilize aberrant angiogenesis for their growth and metastasis and their vessels exhibit vascular hyper‐permeability, we hypothesized that CysLT2R via its actions on endothelium might regulate tumor growth. Both tumor growth and metastases of adoptively transferred syngeneic Lewis lung carcinoma (LLC) cells are significantly reduced in CysLT2R null mice (Cysltr2−/−) compared to WT and CysLT1R null mice (Cysltr1−/−). In WT recipients of LLC cells, CysLT2R expression is significantly increased in the tumor vasculature, compared to CysLT1R. Further, tumor vasculature in Cysltr2−/− recipients exhibited significantly improved integrity as revealed by increased pericyte coverage and decreased leakage of intravenously administered Texas Red‐labeled dextran. Administration of a selective CysLT2R antagonist significantly reduced LLC tumor volume, vessel density, dextran leakage and metastases in WT mice, highlighting CysLT2R as a VEGF‐independent novel regulator of vasculature, promoting risk of metastasis. Thus, both genetic and pharmacologic findings establish CysLT2R as a gateway for angiogenesis and endothelial cell dysregulation in vitro and ex vivo and in vivo model with a mouse tumor. Finally, analysis of primary human lung adenocarcinoma data set revealed a strong correlation between poor survival and high CysLT2R expression, suggesting CysLT2R as a possible target for intervention.Support or Funding InformationJames Foght Professorship Support, AHA GIA 15GRNT 25670004This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Characterization of the Perilipin 5 11‐mer Region
Authors: Tucker Trent M. , Wei Derek T , Tansey John T 
Published: June 2021

Lipid storage‐related diseases have become prevalent throughout the nation and are responsible for afflictions such as obesity and type II diabetes. Proteins such as the perilipin family serve a key role in the modulation of lipolysis. Although this protein family plays such a major role in biochemical processes, little information has been discovered pertaining to the structure of the Perilipins. Structure is central to understanding the function of a protein, and how that protein will interact will other molecules. There has been data showing the structure of the C‐terminal domain of perilipin 3; however, structural information for the other family members is yet, unknown. The current study is aimed to determine the structure of the 11‐mer region in Perilipin 5. The 11‐mer region is implicated in the interactions between Perilipin 5 and lipids. Bioinformatics data were obtained on the 11‐mer sequence. The secondary structure of the 11‐mer region was characterized using Phyre2, and RaptorX and viewed using molecular visualization software including PyMol and NGL. These models predicted the 11‐mer region to have an amphipathic alpha helix which allowed Perilipin 5 to bind to lipid droplets. Additional studies are being performed using protease protection assays and characterization of a synthetic peptide that mimics the 11‐mer region. Characterization on the 11‐mer region of Perilipin 5 will further help elucidate how this region of perilipin 5 associates with lipid droplets.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Correlating Indigenous Peruvian Women's Distance to Cusco and Their Access to Healthcare, and Investigating the Effect of Cat's Claw Extracts on HeLa Cells
Authors: Lamba Arleen , Oakes Alissa , Roberts Lia , Deprele Sylvine , Nogaj Luiza 
Published: June 2021

Uncaria tomentosa, or Cat's Claw, is a large woody vine plant that is indigenous to the Amazonian rain forest. The roots and bark of cat's claw have been used for 2000 years as an herbal remedy for ailments ranging from chronic fatigue to gastrointestinal inflammation, and more recently as an anticancer remedy. To explore the use of Cat's Claw among indigenous women of Peru, the Global Women in STEM Program at Mount Saint Mary's University designed and administered in person a survey that explores socioeconomic factors, access to healthcare, and the use of natural remedies. Survey results showed that Peruvian women often utilize natural remedies to alleviate a wide range of ailments, including cancer. Cat's claw was found to be a common remedy in our survey.Previous chemical analysis of Cat's Claw showed an abundance of polyphenolic compounds such as vanillic acid, gallic acid, and caffeic acid, which are reducing agents. These compounds have been shown to have protective properties against oxidative damage. From the chemical analysis, we hypothesized that both a simple decoction and polyphenolic extract from cat's claw will increase cell viability and decrease cytotoxicity in HeLa cells. In order to test this, we isolated the phenolic compounds of Cat's Claw by soxhlet extraction and compared its effects against previously synthesized vanillic, gallic, and caffeic acids using MTT and LDH Cytotoxicity assays. Our results showed that the purified Cat's Claw extract increased cell viability and decreased cytotoxicity, in comparison to the decocted crude extract. The crude extract exhibited a clear concentration‐dependent trend with a steady decrease in viability and increase in cytotoxicity as the volume of crude extract increased. Similar to the purified extract: the synthesized vanillic, caffeic, and gallic acids showed high cell viability and low cytotoxicity.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High‐Fat Diet Causes Mitochondrial Dysfunction and Renal Fibrosis in Minipigs
Authors: Chien Miao‐Ju , Li Sin‐Jin , Chen Ching‐Yi 
Published: June 2021

Obesity is a common and complex health problem which has been dramatically increasing in the world. It is also considered as an independent risk factor for chronic kidney disease. Kidney is one of the most energy‐demanding organs in the human body, which has the second highest mitochondrial content and oxygen consumption only next to the heart. The purpose of this study was to investigate the nexus between mitochondrial function and kidney injury by using dietary‐induced obese minipig model.Materials and methodsSix‐month‐old Lee‐Sung minipigs were assigned randomly into 2 groups and fed either a control diet (C) or a high‐fat diet (HFD) for six months, the kidney was collected for the analysis.ResultsCompared with C group, HFD group had heavier body weight, thicker back fat, higher plasma levels of glucose, triacylglycerol and total cholesterol. Furthermore, the biomarkers of kidney injury, including blood creatinine, urine creatinine, urine urea, and urine protein were higher in the HFD group than the C ones. A heavier kidney was observed in the HFD pigs; whereas a smaller ratio of kidney weight to body weight was found in the HFD group than C group, implying a less effective loading in the kidney function of HFD pig. In histologic section of kidney, disarranged structure and more glomerular fibrosis were observed in the HFD pigs. Moreover, HFD caused a decreased antioxidant capacity in the kidney, indicating an oxidative stress. Whether HFD caused the renal injury through mitochondrial mechanisms, we analyzed the ATP generation and found that HFD kidney displayed a lower ATP production than C group did. The mitochondrial‐related genes in kidney were analyzed as well. The mRNA expression of SIRT1, which has a role in variety of mitochondrial processes, including redox homeostasis and mitochondrial biogenesis was downregulated by HFD. PGC1‐1a, a nutritional sensor in the kidney, was inhibited by HFD, suggesting a decrease in mitochondrial biogenesis. UCP2, activated by mitochondrial ROS, was upregulated in HFD group compare with C group. The mRNA expressions of Opa1 and Fis1, markers of mitochondrial dynamics, were downregulated by HFD, suggesting a mitochondrial dysfunction.In conclusion, long term HFD feeding in Lee‐Sung minipigs induced obesity, dyslipidemia and renal injury. Mitochondrial dysfunction might partially contribute to the progression of obesity‐related renal damage.Support or Funding InformationThis study was sponsored by the Ministry of Science and Technology, Taiwan (MOST107‐2313‐B‐002‐049).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Development of Enhanced Conformational Sampling Methods for GPCRs
Authors: Serrano Erik , Khleif Rafeed 
Published: June 2021

G protein‐coupled receptors (GPCRs) are known to possess multiple active conformational states in nature, however, studying these conformations is extremely challenging as majority of the functionally important conformations have high energy compared to the lowest energy conformation. We are developing a method called Enhanced Conformational Markov‐state Sampling in Membrane BiLayer Environment (EnCoMSeMBLE) that would enhance our search of the conformational landscape of GPCRs and that can be applied to a‐helical transmembrane proteins in general. It enables a level of conformational sampling not achievable by classical or accelerated molecular dynamics (MD) simulations or Markov‐State Models (MSM). This method combines brute force conformational sampling of helix‐helix interactions in the membrane with MD simulations and Markov‐State modeling to identify functionally important conformations. This method is being tested by application to the Glucagon Like peptide‐1 receptor (GLP1‐R), a class B GPCR, and the muscarinic acetylcholine M2 receptor, a class A GPCR, both of which have been crystallized in inactive as well as active conformations. The comparison of the activation landscapes of class A and class B GPCRs is beginning to provide key similarities and differences in activation across these very distinct GPCRs. This detailed understanding of the GPCR activation, enabled by our method, complements major structural biology efforts underway targeting GPCRs, where it is very challenging to map out the structural landscape and activation pathways of GPCRs.Support or Funding InformationBUILD PODER is supported through a grant from the National Institutes of General Medical Sciences (NIGMS), grants # # 8TL4GM11897This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.