Brain Transport Profiles of Ginsenoside Rb1 by Glucose Transporter 1: In Vitro and in Vivo

Glucosamine (GlcN) is the most widely consumed dietary supplement and exhibits anti-inflammatory effects. However, the influence of GlcN on immune cell generation and function is largely unclear. In this study, GlcN was delivered into mice to examine its biological function in hematopoiesis. We found that GlcN promoted the production of immature myeloid cells, known as myeloid-derived suppressor cells (MDSCs), both in vivo and in vitro. Additionally, GlcN upregulated the expression of glucose transporter 1 in hematopoietic stem and progenitor cells (HSPCs), influenced HSPC functions, and downregulated key genes involved in myelopoiesis. Furthermore, GlcN increased the expression of arginase 1 and inducible nitric oxide synthase to produce high levels of reactive oxygen species, which was regulated by the STAT3 and ERK1/2 pathways, to increase the immunosuppressive ability of MDSCs. We revealed a novel role for GlcN in myelopoiesis and MDSC activity involving a potential link between GlcN and immune system, as well as the new therapeutic benefit.

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Epigenetic upregulation by valproic acid of transferrin receptor 1, and not glucose transporter 1 or CD98hc, at the blood-brain barrier

10.21203/rs.3.rs-1220062/v1 ◽

2022 ◽

Author(s):

Steinunn Sara Helgudóttir ◽

Kasper Bendix Johnsen ◽

Lisa Juul Routhe ◽

Charlotte L.M. Rasmussen ◽

Azra Karamehmedovic ◽

...

Keyword(s):

Valproic Acid ◽

Endothelial Cells ◽

Protein Expression ◽

Transferrin Receptor ◽

Glucose Transporter ◽

Brain Capillaries ◽

Glucose Transporter 1 ◽

Transferrin Receptor 1

Abstract BackgroundThe objectives of the present study were to investigate whether the expression of transferrin receptor 1 (TfR1), glucose transporter 1 (Glut1), or Cluster of Differentiation 98 Heavy Chain (CD98hc) is epigenetically regulated in brain capillary endothelial cells (BCECs) denoting the blood-brain barrier (BBB).MethodsThe expression of these targets was investigated both in vitro and in vivo following treatment with the histone deacetylase inhibitor (HDACi) valproic acid (VPA). Mice were injected intraperitoneally with VPA followed by analysis of isolated brain capillaries, and the capillary depleted brain samples. Brain tissue, isolated brain capillaries, and cultured primary endothelial cells were analyzed by RT-qPCR, immunolabeling and ELISA for expression of TfR1, Glut1 and CD98hc. We also studied the vascular targeting in VPA-treated mice injected with monoclonal anti-transferrin receptor (Ri7) conjugated with 1.4 nm gold nanoparticles. ResultsValidating the effects of VPA on gene transcription in BCECs, transcriptomic analysis identified 24,371 expressed genes, of which 305 were differentially expressed with 192 upregulated and 113 downregulated genes. In vitro using BCECs co-cultured with glial cells, the mRNA expression of Tfrc was significantly higher after VPA treatment for 6 h with its expression returning to baseline after 24 h. Conversely, the mRNA expression of Glut1 and Cd98hc was unaffected by VPA treatment. In vivo, the TfR1 protein expression in brain capillaries increased significantly after treatment with both 100 mg/kg and 400 mg/kg VPA. Conversely, VPA treatment did not increase GLUT1 or CD98hc. Using ICP-MS-based quantification, the brain uptake of nanogold conjugated anti-TfR1 antibodies was non-significant in spite of increased expression of TfR1. ConclusionsWe report that VPA treatment upregulates TfR1 at the BBB both in vivo and in vitro in isolated primary endothelial cells. In contrast, VPA treatment does not influence the expression of GLUT1 and CD98hc. The increase in the overall TfR1 protein expression however does not increase transport of TfR-targeted monoclonal antibody and indicates that targeted delivery using the transferrin receptor should aim for increased mobilization of already available transferrin receptor molecules to improve trafficking through the BBB.

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High concentration of glucose decreases glucose transporter-1 expression in mouse placenta in vitro and in vivo

Journal of Endocrinology ◽

10.1677/joe.0.1600443 ◽

1999 ◽

Vol 160 (3) ◽

pp. 443-452 ◽

Cited By ~ 27

Author(s):

K Ogura ◽

M Sakata ◽

M Yamaguchi ◽

H Kurachi ◽

Y Murata

Keyword(s):

Glucose Concentration ◽

Glucose Transporter ◽

Cytochalasin B ◽

High Concentration ◽

Glucose Transporter 1 ◽

Protein Levels ◽

Placental Cells ◽

Glut1 Mrna

Facilitative glucose transporter-1 (GLUT1) is expressed abundantly and has an important role in glucose transfer in placentas. However, little is known about the regulation of GLUT1 expression in placental cells. We studied the changes in placental GLUT1 levels in relation to changes in glucose concentration in vitro and in vivo. In in vitro experiments, dispersed mouse placental cells were incubated under control (5.5 mM) and moderately high (22 mM) glucose concentrations, and 2-deoxyglucose uptake into cells was studied on days 1-5 of culture. After 4 days of incubation under both conditions, GLUT1 mRNA and proten levels were examined by Northern and immunoblot analyses. Treatment of cells with 22 mM glucose resulted in a significant decrease in 2-deoxyglucose uptake compared with control, from day 2 to day 5 of culture. Moreover, GLUT1 mRNA and protein levels on day 4 of culture were significantly reduced in cells incubated with 22 mM glucose compared with control. Next, we rendered mice diabetic by administering 200 micrograms/g body weight streptozotocin (STZ) on day 8 of pregnancy. Animals were killed on day 12 of pregnancy and placental tissues were obtained. [3H]Cytochalasin B binding study was carried out to assess total GLUTs, and GLUT1 mRNA and protein were measured as above. [3H]Cytochalasin B binding sites in placentas from STZ-treated mice were significantly less than those in control mice. Northern and immunoblot analyses revealed a significant decrease in GLUT1 mRNA and protein levels in diabetic mice compared with the controls. These findings suggest that the glucose concentration may regulate the expression of placental GLUT1.

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A Small-Molecule Inhibitor of Glucose Transporter 1 Downregulates Glycolysis, Induces Cell-Cycle Arrest, and Inhibits Cancer Cell Growth In Vitro and In Vivo

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-12-0131 ◽

2012 ◽

Vol 11 (8) ◽

pp. 1672-1682 ◽

Cited By ~ 263

Author(s):

Yi Liu ◽

Yanyan Cao ◽

Weihe Zhang ◽

Stephen Bergmeier ◽

Yanrong Qian ◽

...

Keyword(s):

Cell Cycle ◽

Cell Growth ◽

Small Molecule ◽

Glucose Transporter ◽

Cancer Cell Growth ◽

Glucose Transporter 1 ◽

Cycle Arrest ◽

Molecule Inhibitor

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Glucagon-like peptide-2 protects against TPN-induced intestinal hexose malabsorption in enterally refed piglets

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00275.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. G293-G300 ◽

Cited By ~ 29

Author(s):

J. J. Cottrell ◽

B. Stoll ◽

R. K. Buddington ◽

J. E. Stephens ◽

L. Cui ◽

...

Keyword(s):

Glucose Transport ◽

Glucose Transporter ◽

Glucose Absorption ◽

Glucose Transporter 1 ◽

Portal Vein Flow ◽

Glucose Transporter 2 ◽

Glucagon Like Peptide ◽

Portal Veins

Premature infants receiving chronic total parenteral nutrition (TPN) due to feeding intolerance develop intestinal atrophy and reduced nutrient absorption. Although providing the intestinal trophic hormone glucagon-like peptide-2 (GLP-2) during chronic TPN improves intestinal growth and morphology, it is uncertain whether GLP-2 enhances absorptive function. We placed catheters in the carotid artery, jugular and portal veins, duodenum, and a portal vein flow probe in piglets before providing either enteral formula (ENT), TPN or a coinfusion of TPN plus GLP-2 for 6 days. On postoperative day 7, all piglets were fed enterally and digestive functions were evaluated in vivo using dual infusion of enteral (13C) and intravenous (2H) glucose, in vitro by measuring mucosal lactase activity and rates of apical glucose transport, and by assessing the abundances of sodium glucose transporter-1 (SGLT-1) and glucose transporter-2 (GLUT2). Both ENT and GLP-2 pigs had larger intestine weights, longer villi, and higher lactose digestive capacity and in vivo net glucose and galactose absorption compared with TPN alone. These endpoints were similar in ENT and GLP-2 pigs except for a lower intestinal weight and net glucose absorption in GLP-2 compared with ENT pigs. The enhanced hexose absorption in GLP-2 compared with TPN pigs corresponded with higher lactose digestive and apical glucose transport capacities, increased abundance of SGLT-1, but not GLUT-2, and lower intestinal metabolism of [13C]glucose to [13C]lactate. Our findings indicate that GLP-2 treatment during chronic TPN maintains intestinal structure and lactose digestive and hexose absorptive capacities, reduces intestinal hexose metabolism, and may facilitate the transition to enteral feeding in TPN-fed infants.

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Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation

Blood ◽

10.1182/blood-2004-10-3980 ◽

2005 ◽

Vol 105 (12) ◽

pp. 4613-4619 ◽

Cited By ~ 184

Author(s):

Falk Martin ◽

Tobias Linden ◽

Dörthe M. Katschinski ◽

Felix Oehme ◽

Ingo Flamme ◽

...

Keyword(s):

Gene Expression ◽

Glucose Transporter ◽

Iron Concentration ◽

Hypoxia Inducible Factor ◽

Sensory System ◽

Mrna Levels ◽

Copper Binding ◽

Glucose Transporter 1

Abstract Cellular oxygen partial pressure is sensed by a family of prolyl-4-hydroxylase domain (PHD) enzymes that modify hypoxia-inducible factor (HIF)α subunits. Upon hydroxylation under normoxic conditions, HIFα is bound by the von Hippel-Lindau tumor suppressor protein and targeted for proteasomal destruction. Since PHD activity is dependent on oxygen and ferrous iron, HIF-1 mediates not only oxygen- but also iron-regulated transcriptional gene expression. Here we show that copper (CuCl2) stabilizes nuclear HIF-1α under normoxic conditions, resulting in hypoxia-response element (HRE)-dependent reporter gene expression. In in vitro hydroxylation assays CuCl2 inhibited prolyl-4-hydroxylation independently of the iron concentration. Ceruloplasmin, the main copper transport protein in the plasma and a known HIF-1 target in vitro, was also induced in vivo in the liver of hypoxic mice. Both hypoxia and CuCl2 increased ceruloplasmin (as well as vascular endothelial growth factor [VEGF] and glucose transporter 1 [Glut-1]) mRNA levels in hepatoma cells, which was due to transcriptional induction of the ceruloplasmin gene (CP) promoter. In conclusion, our data suggest that PHD/HIF/HRE-dependent gene regulation can serve as a sensory system not only for oxygen and iron but also for copper metabolism, regulating the oxygen-, iron- and copper-binding transport proteins hemoglobin, transferrin, and ceruloplasmin, respectively. (Blood. 2005;105:4613-4619)

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Modulation of Glucose Transporter 1 (GLUT1) Expression Levels Alters Mouse Mammary Tumor Cell Growth In Vitro and In Vivo

PLoS ONE ◽

10.1371/journal.pone.0023205 ◽

2011 ◽

Vol 6 (8) ◽

pp. e23205 ◽

Cited By ~ 115

Author(s):

Christian D. Young ◽

Andrew S. Lewis ◽

Michael C. Rudolph ◽

Marisa D. Ruehle ◽

Matthew R. Jackman ◽

...

Keyword(s):

Cell Growth ◽

Glucose Transporter ◽

Tumor Cell Growth ◽

Mammary Tumor Cell ◽

Glucose Transporter 1 ◽

Mouse Mammary Tumor ◽

Glut1 Expression ◽

Mouse Mammary Tumor Cell

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In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment

International Journal of Molecular Sciences ◽

10.3390/ijms22041748 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1748

Author(s):

Marta Woźniak ◽

Gabriela Pastuch-Gawołek ◽

Sebastian Makuch ◽

Jerzy Wiśniewski ◽

Tibor Krenács ◽

...

Keyword(s):

Breast Cancer ◽

Growth Inhibition ◽

Tumor Cells ◽

Glucose Transporter ◽

Drug Uptake ◽

Growth Delay ◽

Glucose Transporter 1 ◽

Tumor Selectivity

Methotrexate (MTX) is a commonly used antimetabolite, which inhibits folate and DNA synthesis to be effective in the treatment of various malignancies. However, MTX therapy is hindered by the lack of target tumor selectivity. We have designed, synthesized and evaluated a novel glucose–methotrexate conjugate (GLU–MTX) both in vitro and in vivo, in which a cleavable linkage allows intracellular MTX release after selective uptake through glucose transporter−1 (GLUT1). GLU–MTX inhibited the growth of colorectal (DLD-1), breast (MCF-7) and lung (A427) adenocarcinomas, squamous cell carcinoma (SCC-25), osteosarcoma (MG63) cell lines, but not in WI-38 healthy fibroblasts. In tumor cells, GLU–MTX uptake increased 17-fold compared to unconjugated MTX. 4,6-O-ethylidene-α-D-glucose (EDG), a GLUT1 inhibitor, significantly interfered with GLU–MTX induced growth inhibition, suggesting a glucose-mediated drug uptake. Glu-MTX also caused significant tumor growth delay in vivo in breast cancer-bearing mice. These results show that our GLUT-MTX conjugate can be selectively uptake by a range of tumor cells to cause their significant growth inhibition in vitro, which was also confirmed in a breast cancer model in vivo. GLUT1 inhibitor EDG interfered with these effects verifying the selective drug uptake. Accordingly, GLU–MTX offers a considerable tumor selectivity and may offer cancer growth inhibition at reduced toxicity.

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Expression of early development-related genes in bovine nuclear transferred and fertilized embryos

Zygote ◽

10.1017/s0967199403002454 ◽

2003 ◽

Vol 11 (4) ◽

pp. 355-360 ◽

Cited By ~ 21

Author(s):

Sang Hyun Park ◽

Soo-Bong Park ◽

Nam-Hyung Kim

Keyword(s):

Mrna Expression ◽

Early Development ◽

Interleukin 6 ◽

Nuclear Transfer ◽

Glucose Transporter ◽

Expression Patterns ◽

Glucose Transporter 1 ◽

E Cadherin

Cloning efficiency following somatic cell nuclear transfer is very low. In order to obtain insights into this problem, mRNA expression patterns of early development-related genes in nuclear transferred embryos were compared with those obtained from in vivo and in vitro fertilization. Semiquantitative reverse-transcription polymerase chain reaction assay was used to compare the gene expression of, the cell adhesion protein E-cadherin, interleukin -6, heat-shock protein 70.1 and bos taurus apoptosis regulator box-a (Bax). The relative abundances of glucose transporter-1, E-cadherin and interleukin-6 were significantly (P<0.05) higher in in vitro fertilized morulae than in vivo derived morulae. Transcription of the gene encoding octamer-binding transcription factor 4 was higher in blastocysts obtained from in vivo fertilization than in those from in vivo blastocysts. The transcript for Bax was markedly upregulated in blastocysts derived from in vitro production and nuclear transfer procedures compared with in vivo fertilization. These results suggest that alterations in mRNA expression of early development genes are more associated with in vitro culture condition than the nuclear transfer procedure itself.

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