Pathological Significance of GLUT-1 Expression in Breast Cancer Cells in Diabetic and Obese Patients: The French Guiana Study

The prevalence of obesity and type 2 diabetes is higher in French Guiana compared to mainland France. These metabolic disorders are associated with an increased risk of cancer. One of the factors involved is hyperinsulinemia that promotes the action of glucose transporter 1 (GLUT-1). The objective of this study is to characterize the expression of GLUT-1 in breast cancers cells in diabetic and obese patients compared to those who are not and to describe the clinical and histological prognostic factors of breast cancer in this population. We conducted a monocentric study including patients with breast cancer diagnosed between 2014 and 2020. Patients were classified into three groups: diabetes, obesity, and control group. The GLUT-1 expression was assessed by immunohistochemistry. In total, 199 patients were included in this study. The median age was 53.5 years, and the median tumor size was 2.8 cm. Luminal A was the most frequent molecular type (58.1%), followed by the triple-negative type (19.9%). The breast cancer in our population was characterized by a younger age at diagnosis, more aggressive molecular types, and larger tumor size. Thus, we suggest the advancement of the age of breast cancer screening in this territory. A total of 144 patients (31 diabetes, 22 obese, and 91 control group) were included for the study of GLUT-1 expression. Overexpression of GLUT-1 was observed in 60.4% of cases and in all carcinoma in situ lesions. GLUT-1 overexpression was associated with more aggressive cancers. This overexpression is correlated with high histological grade, high proliferation index, and aggressive molecular types. Our study found no difference in GLUT-1 expression between the diabetic or obese patients and the control group. These results highlight the potential role of GLUT-1 as a tumor metabolic prognostic marker and also as an interesting target therapy, independently of patient metabolic disorder.

Assessment of The Association of OCT3/4 With GLUT1 And CD105 In Oral Squamous Cell Carcinoma Using Dual Immunohistochemistry

Background: Oral squamous cell carcinoma (OSCC) is the most common cancer type affecting the oral and maxillofacial region. This study aimed to investigate the role of cancer stem cells (CSCs) in angiogenesis and hypoxic response in OSCC.Methods: This retrospective observational study evaluated 56 cases of OSCC using dual immunohistochemistry. Octamer-binding transcription factor 3/4 (OCT3/4) marker was used for evaluation of CSC activity. Glucose transporter 1 (GLUT1) marker was used to evaluate the hypoxic response and angiogenesis, while endoglin (CD105) was used to evaluate the late stage of angiogenesis and blood vessel formation.Results: Overexpression of both OCT3/4 and GLUT1 was noted in early stage of hypoxic response and angiogenesis in OSCC, indicating the important role of CSCs in this phase. However, despite higher expression of CD105, the expression of CSC markers was not significant in the late stage of tumor progression and angiogenesis.Conclusions: CSCs could play important roles in initial stages of tumor progression and angiogenesis. Further studies are required to discover other biomarkers, their roles, and associated pathways of CSCs in OSCC.

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

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.

In silico, ADMET and Docking Analysis for the Compounds of Chloroform Extract of Tinospora cardifolia (Wild.) Identified by GC-MS and Spectral Analysis for Antidiabetic and Anti-Inflammatory Activity

The present study was aimed to phytochemical and GC-MS analysis for chloroform extract of Tinospora cardifolia. The structure of the compounds was further confirmed by UV-spectroscopy and FTIR study. The in silico study like molecular, physico-chemical and drug likeliness property was carried out by computational approaches for the identified molecules. Further toxicity potential and pharmacokinetic profile were also determined. The study was carried out using OSIRIS data warrior and Swiss ADME tools. The docking analysis was carried out for the antidiabetic and anti-inflammatory profiles. The compounds were targeted for α-glucosidase, peroxisome proliferator-activated receptor, glucose transporter-1, cyclo-oxygenase-1 & 2 inhibitions. There were around 12 compounds identified by GC-MS analysis. All the compounds exhibited moderate to good drug likeliness and pharmacokinetic potentials. The molecules showed a good bioactivity score against enzyme receptors. The ADMET prediction showed PGP and CYP-inhibitory effects with the least toxic profile. The docking analysis showed strong binding affinity of [1S-(1α,3aα,4α,6aα)]-1H,3H-furo[3,4-c]furan tetrahydrophenyl (molecule-7) on targeted proteins under investigation.

Scavenging ROS Decreases Amyloid-beta Levels via Activation of PI3K/Akt/GLUT1 pathway in N2a/APP695swe Cells

Dysregulated glucose metabolism in the brain is considered to be the underlying cause of Alzheimer's disease (AD). Abnormal glucose metabolism in AD is associated with decreased glucose transporter 1 (GLUT1) and GLUT3 in the brain, but the underlying mechanisms remains unclear. Here, we reported that GLUT1 expression was decreased in N2a/APP695swe cells and GLUT3 expression was not significantly changed. Flow Cytometry analysis showed a significant increase of intracellular ROS content in N2a/APP695swe cells and GLUT1 expression was upregulated after treatment with the ROS scavenger N-acetyl-L-Cysteine (NAC). Cellular glucose uptake and ATP levels were reduced following decreased GLUT1 expression and increased after upregulating GLUT1. Western blot analyses showed that phosphorylation of PI3K/Akt pathway decreased in N2a/APP695swe cells. Aβ levels decreased after upregulation of GLUT1 expression and increased after downregulation of GLUT1. After NAC treatment, PI3K/Akt pathway phosphorylation levels and GLUT1 expression were upregulated, glucose uptake and ATP contents were increased, and Aβ levels were decreased. After adding PI3K/Akt pathway inhibitor LY29004, GLUT1 expression was reduced and Aβ levels were increased. Besides, the increased glucose uptake and ATP contents by the Akt activator SC79 were hindered with the GLUT1 inhibitor WZB117. Aβ levels decreased after SC79 treatment and increased after WZB117 treatment. Overall, our data suggest that ROS reduced GLUT1 expression by inhibiting PI3K/Akt pathway activity resulting in impaired glucose metabolism and scavenging ROS prevents Aβ via activation of PI3K/Akt/GLUT1 pathway in N2a/APP695swe cells.

Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials

Plasmodium spp. malaria parasites in the blood stage draw energy from anaerobic glycolysis when multiplying in erythrocytes. They tap the ample glucose supply of the infected host using the erythrocyte glucose transporter 1, GLUT1, and a hexose transporter, HT, of the parasite’s plasma membrane. Per glucose molecule, two lactate anions and two protons are generated as waste that need to be released rapidly from the parasite to prevent blockage of the energy metabolism and acidification of the cytoplasm. Recently, the missing Plasmodium lactate/H+ cotransporter was identified as a member of the exclusively microbial formate–nitrite transporter family, FNT. Screening of an antimalarial compound selection with unknown targets led to the discovery of specific and potent FNT-inhibitors, i.e., pentafluoro-3-hydroxy-pent-2-en-1-ones. Here, we summarize the discovery and further development of this novel class of antimalarials, their modes of binding and action, circumvention of a putative resistance mutation of the FNT target protein, and suitability for in vivo studies using animal malaria models.

Transgenerational impact of aberrant inflammation in rat pregnancy

Children of women with pre-eclampsia have increased risk of cardiovascular (CV) and metabolic disease in adult life. Furthermore, the risk of pregnancy complications is higher in daughters born to women affected by pre-eclampsia than in daughters born after uncomplicated pregnancies. While aberrant inflammation contributes to the pathophysiology of pregnancy complications, including pre-eclampsia, the contribution of maternal inflammation to subsequent risk of CV and metabolic disease as well as pregnancy complications in the offspring remains unclear. Here we demonstrate that 24-week-old female rats (F1) born to dams (F0) exposed to lipopolysaccharide (LPS) during pregnancy (to induce inflammation) exhibited mild systolic dysfunction, increased cardiac growth-related gene expression, abnormal glucose tolerance and coagulopathy; whereas male F1 offspring exhibited abnormal glucose tolerance and increased visceral fat accumulation compared with F1 sex-matched offspring born to saline-treated dams. Both male and female F1 offspring born to LPS-treated dams had evidence of anemia. Fetuses (F2) from F1 females born to LPS-treated dams were growth restricted, and this reduction in fetal growth was associated with increased CD68 positivity and decreased expression of glucose transporter-1 in their utero-placental units. These results indicate that abnormal maternal inflammation can contribute to increased risk of CV and metabolic disease in offspring, and that the effects of inflammation may be transgenerational. This study provides evidence in support of early screening for CV and metabolic disease, as well as pregnancy complications in offspring affected by pre-eclampsia or other pregnancy complications associated with aberrant inflammation.

EgGLUT1 Is Crucial for the Viability of Echinococcus granulosus sensu stricto Metacestode: A New Therapeutic Target?

Cystic echinococcosis (CE) is a zoonotic parasitic disease caused by infection with the larvae of Echinococcus granulosus sensu lato (s.l.) cluster. It is urgent to identify novel drug targets and develop new drug candidates against CE. Glucose transporter 1 (GLUT1) is mainly responsible for the transmembrane transport of glucose to maintain its constant cellular availability and is a recent research hotspot as a drug target in various diseases. However, the role of GLUT1 in E. granulosus s.l. (EgGLUT1) was unknown. In this study, we cloned a conserved GLUT1 homology gene (named EgGLUT1-ss) from E. granulosus sensu stricto (s.s.) and found EgGLUT1-ss was crucial for glucose uptake and viability by the protoscoleces of E. granulosus s.s. WZB117, a GLUT1 inhibitor, inhibited glucose uptake by E. granulosus s.s. and the viability of the metacestode in vitro. In addition, WZB117 showed significant therapeutic activity in E. granulosus s.s.-infected mice: a 10 mg/kg dose of WZB117 significantly reduced the number and weight of parasite cysts (P < 0.05) as efficiently as the reference drug, albendazole. Our results demonstrate that EgGLUT1-ss is crucial for glucose uptake by the protoscoleces of E. granulosus s.s., and its inhibitor WZB117 has a therapeutic effect on CE.

Glucosamine Interferes With Myelopoiesis and Enhances the Immunosuppressive Activity of Myeloid-Derived Suppressor Cells

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.