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Benjamin J Andreone, Brian Wai Chow, Aleksandra Tata, Baptiste Lacoste, Ayal Ben-Zvi, Kevin Bullock, Amy A Deik, David D Ginty, Clary B Clish, Chenghua Gu
The blood-brain barrier (BBB) provides a constant homeostatic brain environment that is essential for proper neural function. An unusually low rate of vesicular transport (transcytosis) has been identified as one of the two unique properties of CNS endothelial cells, relative to peripheral endothelial cells, that maintain the restrictive quality of the BBB. However, it is not known how this low rate of transcytosis is achieved. Here we provide a mechanism whereby the regulation of CNS endothelial cell lipid composition specifically inhibits the caveolae-mediated transcytotic route readily used in the periphery...
April 11, 2017: Neuron
Kohei Yamamizu, Mio Iwasaki, Hitomi Takakubo, Takumi Sakamoto, Takeshi Ikuno, Mami Miyoshi, Takayuki Kondo, Yoichi Nakao, Masato Nakagawa, Haruhisa Inoue, Jun K Yamashita
The blood-brain barrier (BBB) is composed of four cell populations, brain endothelial cells (BECs), pericytes, neurons, and astrocytes. Its role is to precisely regulate the microenvironment of the brain through selective substance crossing. Here we generated an in vitro model of the BBB by differentiating human induced pluripotent stem cells (hiPSCs) into all four populations. When the four hiPSC-derived populations were co-cultured, endothelial cells (ECs) were endowed with features consistent with BECs, including a high expression of nutrient transporters (CAT3, MFSD2A) and efflux transporters (ABCA1, BCRP, PGP, MRP5), and strong barrier function based on tight junctions...
March 14, 2017: Stem Cell Reports
F Ungaro, C Tacconi, C Correale, L Massimino, P Corsetto, A Piontini, P Fonteyne, F Calcaterra, S Della Bella, A Spinelli, M Carvello, A Rizzo, S Vetrano, G Fiorino, F Furfaro, K R Maddipati, S D'Alessio, S Danese
No abstract text is available yet for this article.
February 1, 2017: Journal of Crohn's & Colitis
Hiroshi Moritake, Megumi Obara, Yusuke Saito, Ayako Kashimada, Masatoshi Takagi, Megumi Funakoshi-Tago, Tomofusa Fukuyama, Mikio Yoshioka, Akira Inoue, Hiroyuki Komatsu, Hideki Nishitoh, Hiroaki Kataoka, Hiroyuki Nunoi
Major facilitator superfamily domain containing 2a (Mfsd2a) is a member of the major facilitator superfamily. Mfsd2a functions as a transporter for docosahexaenoic acid and also plays a role in the unfolded protein response (UPR) upon tunicamycin (TM) exposure. UPR is involved in the pathogenesis of various human diseases. TM and thapsigargin are representative experimental reagents that induce UPR. To elucidate the detailed function of Mfsd2a in UPR in vivo, we generated Mfsd2a-deficient mice and investigated the role of Mfsd2a during UPR induced by TM or thapsigargin...
April 2017: Human Cell
Anna M Pauter, Sofia Trattner, Amanda Gonzalez-Bengtsson, Emanuela Talamonti, Abolfazl Asadi, Olga Dethlefsen, Anders Jacobsson
The molecular details relevant to dietary supplementation of the omega-3 fatty acid DHA in mothers as well as in their offspring are not clear. The PUFA elongase, elongation of very long-chain fatty acid (ELOVL)2, is a critical enzyme in the formation of DHA in mammals. In order to address the question regarding the origin of DHA during perinatal life, we have used DHA-deficient Elovl2-ablated mice as a model system to analyze the maternal impact on the DHA level in their offspring of various genotypes. Elovl2(-/-) mothers maintained on control diet had significantly lower systemic levels of DHA compared with the Elovl2(+/-) and Elovl2(+/+) mothers...
January 2017: Journal of Lipid Research
Wenjuan Pu, Hui Zhang, Xiuzhen Huang, Xueying Tian, Lingjuan He, Yue Wang, Libo Zhang, Qiaozhen Liu, Yan Li, Yi Li, Huan Zhao, Kuo Liu, Jie Lu, Yingqun Zhou, Pengyu Huang, Yu Nie, Yan Yan, Lijian Hui, Kathy O Lui, Bin Zhou
Hepatocytes are functionally heterogeneous and are divided into two distinct populations based on their metabolic zonation: the periportal and pericentral hepatocytes. During liver injury and regeneration, the cellular dynamics of these two distinct populations remain largely elusive. Here we show that major facilitator super family domain containing 2a (Mfsd2a), previously known to maintain blood-brain barrier function, is a periportal zonation marker. By genetic lineage tracing of Mfsd2a(+) periportal hepatocytes, we show that Mfsd2a(+) population decreases during liver homeostasis...
November 18, 2016: Nature Communications
Bernice H Wong, Jia Pei Chan, Amaury Cazenave-Gassiot, Rebecca W Poh, Juat Chin Foo, Dwight L A Galam, Sujoy Ghosh, Long N Nguyen, Veluchamy A Barathi, Sia W Yeo, Chi D Luu, Markus R Wenk, David L Silver
Eye photoreceptor membrane discs in outer rod segments are highly enriched in the visual pigment rhodopsin and the ω-3 fatty acid docosahexaenoic acid (DHA). The eye acquires DHA from blood, but transporters for DHA uptake across the blood-retinal barrier or retinal pigment epithelium have not been identified. Mfsd2a is a newly described sodium-dependent lysophosphatidylcholine (LPC) symporter expressed at the blood-brain barrier that transports LPCs containing DHA and other long-chain fatty acids. LPC transport via Mfsd2a has been shown to be necessary for human brain growth...
May 13, 2016: Journal of Biological Chemistry
Debra Q Y Quek, Long N Nguyen, Hao Fan, David L Silver
Major facilitator superfamily domain containing 2A (MFSD2A) was recently characterized as a sodium-dependent lysophosphatidylcholine transporter expressed at the blood-brain barrier endothelium. It is the primary route for importation of docosohexaenoic acid and other long-chain fatty acids into fetal and adult brain and is essential for mouse and human brain growth and function. Remarkably, MFSD2A is the first identified major facilitator superfamily member that uniquely transports lipids, implying that MFSD2A harbors unique structural features and transport mechanism...
April 29, 2016: Journal of Biological Chemistry
María T Prieto-Sánchez, María Ruiz-Palacios, José E Blanco-Carnero, Ana Pagan, Christian Hellmuth, Olaf Uhl, Wolfgang Peissner, Antonio J Ruiz-Alcaraz, Juan J Parrilla, Berthold Koletzko, Elvira Larqué
BACKGROUND & AIMS: Maternal-fetal transfer of docosahexaenoic acid (DHA) is impaired by gestational diabetes mellitus (GDM), but the underlying mechanisms are still unknown. MFSD2a was recently recognized as a lyso-phospholipid (lyso-PL) transporter that facilitates DHA accretion in brain. The role of this transporter in placenta is uncertain. We evaluated effects of GDM and its treatment (diet or insulin) on phospholipid species, fatty acid profile in women, cord blood and placental fatty acid carriers...
January 29, 2016: Clinical Nutrition: Official Journal of the European Society of Parenteral and Enteral Nutrition
Lina Cui, Huiying Wang, Xiaoyin Lu, Rui Wang, Ru Zheng, Yue Li, Xiaokui Yang, Wen-Tong Jia, Yangyu Zhao, Yongqing Wang, Haibin Wang, Yan-Ling Wang, Cheng Zhu, Hai-Yan Lin, Hongmei Wang
The placental syncytiotrophoblast, which is formed by the fusion of cytotrophoblast cells, is indispensable for the establishment and maintenance of normal pregnancy. The human endogenous retrovirus envelope glycoprotein syncytin-2 is the most important player in mediating trophoblast cell-cell fusion as a fusogen. We constructed expression plasmids of wild-type and 21 single-amino-acid substitution mutants of syncytin-2, including 10 N-glycosylation sites individually silenced by mutagenizing N to Q, 1 naturally occurring single-nucleotide polymorphism (SNP) N118S that introduced an N-glycosylation site, and another 10 non-synonymous SNPs located within important functional domains...
March 3, 2016: Cell Adhesion & Migration
Jing-Zhang Wang, Ning Xiao, Ying-Zhou Zhang, Chao-Xian Zhao, Xin-Hua Guo, Li-Min Lu
The blood-brain barrier (BBB) keeps the central nervous system (CNS) safe from various brain diseases, while the BBB makes it difficult for effective drugs to enter the CNS. Mfsd2a is specifically expressed on the cell membrane of brain-microvascular endothelial cell (BMEC) and is implicated in the delivery of some substances across the BBB. Mfsd2a is the first inhibitor of the transcytosis and the first transporter for lysophosphatidylcholine-docosahexaenoic acid (LPC-DHA) in BMECs. The crucial dual function of Mfsd2a puts forward two kinds of Mfsd2a-based strategies for carrying drugs from blood to the CNS...
February 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Qin Zhou, Yuanyan Xiong, Xiao R Huang, Patrick Tang, Xueqing Yu, Hui Y Lan
Transforming growth factor-β/Smad3 signaling plays a critical role in the process of chronic kidney disease (CKD), but targeting Smad3 systematically may cause autoimmune disease by impairing immunity. In this study, we used whole-transcriptome RNA-sequencing to identify the differential gene expression profile, gene ontology, pathways, and alternative splicing related to TGF-β/Smad3 in CKD. To explore common dysregulation of genes associated with Smad3-dependent renal injury, kidney tissues of Smad3 wild-type and knockout mice with immune (anti-glomerular basement membrane glomerulonephritis) and non-immune (obstructive nephropathy)-mediated CKD were used for RNA-sequencing analysis...
December 9, 2015: Scientific Reports
Christer Betsholtz
How the human brain rapidly builds up its lipid content during brain growth and maintains its lipids in adulthood has remained elusive. Two new studies show that inactivating mutations in MFSD2A, known to be expressed specifically at the blood-brain barrier, lead to microcephaly, thereby offering a simple and surprising solution to an old enigma.
July 2015: Nature Genetics
Alicia Guemez-Gamboa, Long N Nguyen, Hongbo Yang, Maha S Zaki, Majdi Kara, Tawfeg Ben-Omran, Naiara Akizu, Rasim Ozgur Rosti, Basak Rosti, Eric Scott, Jana Schroth, Brett Copeland, Keith K Vaux, Amaury Cazenave-Gassiot, Debra Q Y Quek, Bernice H Wong, Bryan C Tan, Markus R Wenk, Murat Gunel, Stacey Gabriel, Neil C Chi, David L Silver, Joseph G Gleeson
Docosahexanoic acid (DHA) is the most abundant omega-3 fatty acid in brain, and, although it is considered essential, deficiency has not been linked to disease. Despite the large mass of DHA in phospholipids, the brain does not synthesize it. DHA is imported across the blood-brain barrier (BBB) through the major facilitator superfamily domain-containing 2a (MFSD2A) protein. MFSD2A transports DHA as well as other fatty acids in the form of lysophosphatidylcholine (LPC). We identify two families displaying MFSD2A mutations in conserved residues...
July 2015: Nature Genetics
Vafa Alakbarzade, Abdul Hameed, Debra Q Y Quek, Barry A Chioza, Emma L Baple, Amaury Cazenave-Gassiot, Long N Nguyen, Markus R Wenk, Arshia Q Ahmad, Ajith Sreekantan-Nair, Michael N Weedon, Phil Rich, Michael A Patton, Thomas T Warner, David L Silver, Andrew H Crosby
The major pathway by which the brain obtains essential omega-3 fatty acids from the circulation is through a sodium-dependent lysophosphatidylcholine (LPC) transporter (MFSD2A), expressed in the endothelium of the blood-brain barrier. Here we show that a homozygous mutation affecting a highly conserved MFSD2A residue (p.Ser339Leu) is associated with a progressive microcephaly syndrome characterized by intellectual disability, spasticity and absent speech. We show that the p.Ser339Leu alteration does not affect protein or cell surface expression but rather significantly reduces, although not completely abolishes, transporter activity...
July 2015: Nature Genetics
Eri Segi-Nishida
No abstract text is available yet for this article.
November 2014: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
Leah C Byrne, Yvonne J Lin, Trevor Lee, David V Schaffer, John G Flannery
Systemic delivery of AAV9 offers the potential for widespread and efficient gene delivery to the retina, and may thus be a useful approach for treatment of disease where intraocular injections are not possible, for syndromes affecting multiple organs, or where early intervention is required. The expression resulting from intravenous injection of AAV9 is more efficient in neonates than adults, and here we characterize the effect of age on retinal transduction of AAV9 in the mouse retina. We find that the pattern of expression in neonatal mice is correlated to the development of the retinal vasculature, and that the area of the retinal transduction as well as the cell types infected vary depending on the age at injection...
February 2015: Molecular Therapy: the Journal of the American Society of Gene Therapy
Zhen Zhao, Berislav V Zlokovic
Two recent papers in Nature, Ben-Zvi et al. (2014) and Nguyen et al. (2014), report a surprising dual role for the blood-brain barrier transporter MFSD2A in both establishing BBB integrity and in uptake of the fatty acid DHA.
May 21, 2014: Neuron
Long N Nguyen, Dongliang Ma, Guanghou Shui, Peiyan Wong, Amaury Cazenave-Gassiot, Xiaodong Zhang, Markus R Wenk, Eyleen L K Goh, David L Silver
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is essential for normal brain growth and cognitive function. Consistent with its importance in the brain, DHA is highly enriched in brain phospholipids. Despite being an abundant fatty acid in brain phospholipids, DHA cannot be de novo synthesized in brain and must be imported across the blood-brain barrier, but mechanisms for DHA uptake in brain have remained enigmatic. Here we identify a member of the major facilitator superfamily--Mfsd2a (previously an orphan transporter)--as the major transporter for DHA uptake into brain...
May 22, 2014: Nature
Ayal Ben-Zvi, Baptiste Lacoste, Esther Kur, Benjamin J Andreone, Yoav Mayshar, Han Yan, Chenghua Gu
The central nervous system (CNS) requires a tightly controlled environment free of toxins and pathogens to provide the proper chemical composition for neural function. This environment is maintained by the 'blood-brain barrier' (BBB), which is composed of blood vessels whose endothelial cells display specialized tight junctions and extremely low rates of transcellular vesicular transport (transcytosis). In concert with pericytes and astrocytes, this unique brain endothelial physiological barrier seals the CNS and controls substance influx and efflux...
May 22, 2014: Nature
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