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1
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Emam AAM, Eyada MMK, Gomaa AHA, Abd El-Fadeal NM, Ibrahim GH, El-Kherbetawy MK, Tawfik NZ. Glucose transporter-1 (GLUT-1) upregulation in vitiligo: A possible link to skin depigmentation. Gene 2025; 950:149383. [PMID: 40032057 DOI: 10.1016/j.gene.2025.149383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 02/27/2025] [Accepted: 02/28/2025] [Indexed: 03/05/2025]
Abstract
BACKGROUND Vitiligo is a prevalent autoimmune skin disorder characterized by progressive depigmented patches of the skin and/or mucosa. Lately, extensive research has been investigating molecular pathogenesis underlying vitiligo, epidermal-immune cell crosstalk, structural aberrations in cellular skin components and immune cell metabolism derangements. Glucose transporter-1 (GLUT-1) has recently proved to be increased in proinflammatory conditions and autoimmune diseases. GLUT-1 expression is upregulated in rheumatoid arthritis, systemic lupus erythematosus, psoriasis and chronic spongiotic dermatitis. OBJECTIVE To investigate GLUT-1 expression in vitiligo. SUBJECTS AND METHODS The study included 30 vitiligo patients "vitiligo vulgaris" and 30 healthy individuals. Biopsies of the patients' lesional vitiligo skin and the control group's normal skin were obtained. They were all tested for GLUT-1 mRNA expression using real-time polymerase chain reaction (RT-PCR) and GLUT-1 antibody expression using immunohistochemistry (IHC). Hematoxylin and eosin (H&E) staining for the specimens was additionally done for histopathological assessment. RESULTS GLUT-1 expression was upregulated in lesional skin of vitiligo patients compared to normal control skin (P-value < 0.001). Also, lesional specimens from stable disease showed more GLUT-1 expression than active disease but without a significant difference (P-value = 0.283). There was no significant correlation between the proposed vitiligo histological scoring system and vitiligo signs of the disease activity score. CONCLUSION GLUT-1 could play a crucial role in vitiligo disease onset, persistence and progression, through keratinocyte-melanocyte-fibroblast-immune cell crosstalk, being the initially deranged metabolic pathway for all these cells giving an insight into vitiligo metabolomics.
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Affiliation(s)
- Amira A M Emam
- Department of Dermatology, Venereology and Andrology Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt.
| | - Moustafa M K Eyada
- Department of Dermatology, Venereology and Andrology Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt.
| | - Amal H A Gomaa
- Department of Dermatology, Venereology and Andrology Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt.
| | - Noha M Abd El-Fadeal
- Department of Medical Biochemistry and Molecular Biology Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt; Biochemistry Department, Ibn Sina National College for Medical Studies, Jeddah 22421, Saudi Arabia.
| | - Gehan H Ibrahim
- Department of Medical Biochemistry and Molecular Biology Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt; Faculty of Medicine, King Salman International University, El Tur, South Sinai 46511, Egypt.
| | | | - Noha Z Tawfik
- Department of Dermatology, Venereology and Andrology Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt.
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2
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Wu L, Ji Y, Lei F. Two-Step Loss of GLUTs in the High-Metabolism Passerines. Integr Zool 2025. [PMID: 39940071 DOI: 10.1111/1749-4877.12958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/27/2024] [Accepted: 01/16/2025] [Indexed: 02/14/2025]
Abstract
Glucose transporters (GLUTs) play vital roles in cellular metabolism. Understanding their evolutionary dynamics in birds is essential for elucidating avian physiology and adaptation. However, the choice of gene detection method in gene family analysis may affect the conclusion. Here, we present a comprehensive investigation of methodologies and GLUT gene loss events in avian lineages, focusing on the loss of GLUT4 and GLUT8. To illustrate the effects of these methods, we first employed BUSCO-based homolog identification, calculated pairwise evolutionary distances between different species, and performed separate blastn and blastp searches to identify homologs in two groups of animals. Our analyses revealed a significant decline in blastn accuracy with increasing evolutionary distance, represented by relative divergence times. Through a more robust blastp-based gene detection pipeline, we provide evidence for the loss of GLUT genes in birds based on 58 vertebrate genomes, including 47 bird species. Our results support the reported early loss of GLUT4 in Aves. We also newly emphasize the absence of GLUT8 in passerines, potentially due to adaptation to high-sugar diets in their ancestors. These findings enhance our knowledge of avian metabolism and the evolution of GLUT genes.
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Affiliation(s)
- Lei Wu
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yanzhu Ji
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Fumin Lei
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
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3
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Liu G, Ji Y. Electrochemiluminescent evaluation of GLUT4 expression in rat adipocytes induced by Ganoderma lucidum polysaccharides. Int J Biol Macromol 2024; 270:132106. [PMID: 38734335 DOI: 10.1016/j.ijbiomac.2024.132106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 05/01/2024] [Accepted: 05/03/2024] [Indexed: 05/13/2024]
Abstract
Glucose transporter 4 (GLUT4) directly facilitates cellular uptake of glucose and plays a crucial role in mammalian adipose tissue glucose metabolism. In this work, we constructed a cytosensor for sensitive electrochemiluminescence (ECL) detection of GLUT4 in rat adipocytes (RA cells). A carbon nanotube sponge (CNTSP) was selected to fabricate a permeable electrode to overcome the steric hindrance of cells on the electrode. The expression of GLUT4 after treatment with Ganoderma lucidum polysaccharide (GLP) was assessed by analyzing the luminescence emitted from cell-surface ECL probes. Our preliminary results suggest that GLP promote the expression of GLUT4, thereby enhancing the uptake of the fluorescent glucose 2-NBDG. Treatment with GLP affected GLUT4 expression in RA cells in a dose-dependent manner. Additionally, the ECL cytosensor contributes to the development of ECL imaging of receptors on the cell surface for clinical drug evaluation.
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Affiliation(s)
- Gen Liu
- Key Laboratory of Green and Precise Synthetic Chemistry and Applications, Ministry of Education, School of Chemistry and Materials Science, Huaibei Normal University, Huaibei, Anhui 235000, PR China.
| | - Yahui Ji
- Key Laboratory of Green and Precise Synthetic Chemistry and Applications, Ministry of Education, School of Chemistry and Materials Science, Huaibei Normal University, Huaibei, Anhui 235000, PR China
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4
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Lazniewska J, Li KL, Johnson IRD, Sorvina A, Logan JM, Martini C, Moore C, Ung BSY, Karageorgos L, Hickey SM, Prabhakaran S, Heatlie JK, Brooks RD, Huzzell C, Warnock NI, Ward MP, Mohammed B, Tewari P, Martin C, O'Toole S, Edgerton LB, Bates M, Moretti P, Pitson SM, Selemidis S, Butler LM, O'Leary JJ, Brooks DA. Dynamic interplay between sortilin and syndecan-1 contributes to prostate cancer progression. Sci Rep 2023; 13:13489. [PMID: 37596305 PMCID: PMC10439187 DOI: 10.1038/s41598-023-40347-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 08/09/2023] [Indexed: 08/20/2023] Open
Abstract
Prostate cancer (PCa) development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor expression and signalling. Defining the molecular mechanism that underpins this metabolic programming will have direct significance for patients with PCa who have a poor prognosis. Here we show that there is a dynamic balance between sortilin and syndecan-1, that reports on different metabolic phenotypes. Using tissue microarrays, we demonstrated by immunohistochemistry that sortilin was highly expressed in low-grade cancer, while syndecan-1 was upregulated in high-grade disease. Mechanistic studies in prostate cell lines revealed that in androgen-sensitive LNCaP cells, sortilin enhanced glucose metabolism by regulating GLUT1 and GLUT4, while binding progranulin and lipoprotein lipase (LPL) to limit lipid metabolism. In contrast, in androgen-insensitive PC3 cells, syndecan-1 was upregulated, interacted with LPL and colocalised with β3 integrin to promote lipid metabolism. In addition, androgen-deprived LNCaP cells had decreased expression of sortilin and reduced glucose-metabolism, but increased syndecan-1 expression, facilitating interactions with LPL and possibly β3 integrin. We report a hitherto unappreciated molecular mechanism for PCa, which may have significance for disease progression and how androgen-deprivation therapy might promote castration-resistant PCa.
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Affiliation(s)
- Joanna Lazniewska
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
| | - Ka Lok Li
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Ian R D Johnson
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Alexandra Sorvina
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Jessica M Logan
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Carmela Martini
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Courtney Moore
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Ben S-Y Ung
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Litsa Karageorgos
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Shane M Hickey
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Sarita Prabhakaran
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia
- Department of Anatomical Pathology, College of Medicine and Public Health, Flinders University, Bedford Park, SA, 5042, Australia
| | - Jessica K Heatlie
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Robert D Brooks
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Chelsea Huzzell
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Nicholas I Warnock
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, 5000, Australia
| | - Mark P Ward
- Department of Histopathology, Trinity College Dublin, Dublin 8, Ireland
| | - Bashir Mohammed
- Department of Histopathology, Trinity College Dublin, Dublin 8, Ireland
| | - Prerna Tewari
- Department of Histopathology, Trinity College Dublin, Dublin 8, Ireland
| | - Cara Martin
- Department of Histopathology, Trinity College Dublin, Dublin 8, Ireland
| | - Sharon O'Toole
- Department of Histopathology, Trinity College Dublin, Dublin 8, Ireland
| | | | - Mark Bates
- Department of Histopathology, Trinity College Dublin, Dublin 8, Ireland
| | - Paul Moretti
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, 5000, Australia
| | - Stuart M Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, 5000, Australia
| | - Stavros Selemidis
- School of Health and Biomedical Sciences, STEM College, RMIT University, Bundoora, VIC, 3083, Australia
| | - Lisa M Butler
- South Australian ImmunoGENomics Cancer Institute and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA, 5000, Australia
- Solid Tumour Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia
| | - John J O'Leary
- Department of Histopathology, Trinity College Dublin, Dublin 8, Ireland
| | - Douglas A Brooks
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
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5
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Gora N, Weselinski LJ, Begoyan VV, Cooper A, Choe JY, Tanasova M. Discrimination of GLUTs by Fructose Isomers Enables Simultaneous Screening of GLUT5 and GLUT2 Activity in Live Cells. ACS Chem Biol 2023; 18:1089-1100. [PMID: 37116192 PMCID: PMC10566446 DOI: 10.1021/acschembio.2c00682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2023]
Abstract
Facilitative carbohydrate transporters (GLUTs, SLC2 gene family) are transmembrane proteins transporting hexoses and other sugars based on cellular metabolic demands. While a direct link between GLUTs and metabolic disorders has framed them as important biological and medicinal targets, targeting disease-relevant GLUTs remains challenging. In this study, we aimed to identify substrate-GLUT interactions that would discriminate between major fructose transporters. We examined the uptake distribution for conformational and configurational isomers of fructose using the corresponding conformationally locked fluorescently labeled mimetics as probes for assessing GLUT preferences in real time. Through comparative analysis of the uptake of the probes in the yeast-based single GLUT expression systems and the multi-GLUT mammalian cell environment, we established the ability of fructose transporters to discriminate between fructose conformers and epimers. We demonstrated that recreating the conformational and configurational mixture of fructose with molecular probes allows for the specific probe distribution, with fructofuranose mimetic being taken up preferentially through GLUT5 and β-d-fructopyranose mimetic passing through GLUT2. The uptake of α-d-fructopyranose mimetic was found to be independent of GLUT5 or GLUT2. The results of this study provide a new approach to analyzing GLUT5 and GLUT2 activity in live cells, and the findings can be used as a proof-of-concept for multi-GLUT activity screening in live cells. The research also provides new knowledge on substrate-GLUT interactions and new tools for monitoring alterations in GLUT activities.
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Affiliation(s)
- Nazar Gora
- Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, Michigan 49931, United States
- Health Research Institute, Michigan Technological University, 1400 Townsend Drive, Houghton, Michigan 49931, United States
| | - Lukasz J Weselinski
- Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, Michigan 49931, United States
| | - Vagarshak V Begoyan
- Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, Michigan 49931, United States
| | - Andrew Cooper
- Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, Michigan 49931, United States
| | - Jun-Yong Choe
- Department of Chemistry, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina 27834, United States
- Department of Biochemistry and Molecular Biology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, United States
| | - Marina Tanasova
- Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, Michigan 49931, United States
- Health Research Institute, Michigan Technological University, 1400 Townsend Drive, Houghton, Michigan 49931, United States
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6
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Rana N, Aziz MA, Serya RAT, Lasheen DS, Samir N, Wuest F, Abouzid KAM, West FG. A Fluorescence-Based Assay to Probe Inhibitory Effect of Fructose Mimics on GLUT5 Transport in Breast Cancer Cells. ACS BIO & MED CHEM AU 2023; 3:51-61. [PMID: 37101605 PMCID: PMC10125380 DOI: 10.1021/acsbiomedchemau.2c00056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 10/20/2022] [Accepted: 10/20/2022] [Indexed: 04/28/2023]
Abstract
Rapid cell division and reprogramming of energy metabolism are two crucial hallmarks of cancer cells. In humans, hexose trafficking into cancer cells is mainly mediated through a family of glucose transporters (GLUTs), which are facilitative transmembrane hexose transporter proteins. In several breast cancers, fructose can functionally substitute glucose as an alternative energy supply supporting rapid proliferation. GLUT5, the principal fructose transporter, is overexpressed in human breast cancer cells, providing valuable targets for breast cancer detection as well as selective targeting of anticancer drugs using structurally modified fructose mimics. Herein, a novel fluorescence assay was designed aiming to screen a series of C-3 modified 2,5-anhydromannitol (2,5-AM) compounds as d-fructose analogues to explore GLUT5 binding site requirements. The synthesized probes were evaluated for their ability to inhibit the uptake of the fluorescently labeled d-fructose derivative 6-NBDF into EMT6 murine breast cancer cells. A few of the compounds screened demonstrated highly potent single-digit micromolar inhibition of 6-NBDF cellular uptake, which was substantially more potent than the natural substrate d-fructose, at a level of 100-fold or more. The results of this assay are consistent with those obtained from a previous study conducted for some selected compounds against 18F-labeled d-fructose-based probe 6-[18F]FDF, indicating the reproducibility of the current non-radiolabeled assay. These highly potent compounds assessed against 6-NBDF open avenues for the development of more potent probes targeting GLUT5-expressing cancerous cells.
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Affiliation(s)
- Natasha Rana
- Department
of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada
- Department
of Oncology, University of Alberta—Cross
Cancer Institute, Edmonton, AB T6G IZ2, Canada
- Cancer
Research Institute of Northern Alberta, University of Alberta, 2-132 Li Ka Shing, Edmonton, AB T6G 2E1, Canada
| | - Marwa A. Aziz
- Department
of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abassia, P.O. Box 11566, Cairo 11566, Egypt
| | - Rabah A. T. Serya
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abassia, P.O. Box 11566, Cairo 11566, Egypt
| | - Deena S. Lasheen
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abassia, P.O. Box 11566, Cairo 11566, Egypt
| | - Nermin Samir
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abassia, P.O. Box 11566, Cairo 11566, Egypt
| | - Frank Wuest
- Department
of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada
- Department
of Oncology, University of Alberta—Cross
Cancer Institute, Edmonton, AB T6G IZ2, Canada
| | - Khaled A. M. Abouzid
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abassia, P.O. Box 11566, Cairo 11566, Egypt
| | - F. G. West
- Department
of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada
- Department
of Oncology, University of Alberta—Cross
Cancer Institute, Edmonton, AB T6G IZ2, Canada
- Cancer
Research Institute of Northern Alberta, University of Alberta, 2-132 Li Ka Shing, Edmonton, AB T6G 2E1, Canada
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7
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Kalhor S, Fattahi A. Design of ionic liquids containing glucose and choline as drug carriers, finding the link between QM and MD studies. Sci Rep 2022; 12:21941. [PMID: 36535965 PMCID: PMC9763358 DOI: 10.1038/s41598-022-25963-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022] Open
Abstract
Designing drug delivery systems for therapeutic compounds whose receptors are located in the cytosol of cells is challenging as a bilayer cell membrane is negatively charged. The newly designed drug delivery systems should assist the mentioned drugs in passing the membrane barriers and achieving their targets. This study concentrated on developing novel ionic liquids (ILs) that interact effectively with cell membranes. These ILs are based on glucose-containing choline and are expected to be non-toxic. The binding energies of the known pharmaceutically active ionic liquids were calculated at the B3LYP/6-311++G(d,p) level in the gas phase and compared with those of our newly designed carbohydrate-based ionic liquids. Subsequently, we employed MD simulations to obtain information about the interactions of these known and designed ILs with the cell membrane. In our approach, we adopted QM and MD studies and illustrated that there could be a link between the QM and MD results.
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Affiliation(s)
- Sepideh Kalhor
- Department of Chemistry, Sharif University of Technology, Tehran, Iran
| | - Alireza Fattahi
- Department of Chemistry, Sharif University of Technology, Tehran, Iran.
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8
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Sheinboim D, Parikh S, Manich P, Markus I, Dahan S, Parikh R, Stubbs E, Cohen G, Zemser-Werner V, Bell RE, Ruiz SA, Percik R, Brenner R, Leibou S, Vaknine H, Arad G, Gerber Y, Keinan-Boker L, Shimony T, Bikovski L, Goldstein N, Constantini K, Labes S, Mordechai S, Doron H, Lonescu A, Ziv T, Nizri E, Choshen G, Eldar-Finkelman H, Tabach Y, Helman A, Ben-Eliyahu S, Erez N, Perlson E, Geiger T, Ben-Zvi D, Khaled M, Gepner Y, Levy C. An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination. Cancer Res 2022; 82:4164-4178. [PMID: 36084256 PMCID: PMC9762351 DOI: 10.1158/0008-5472.can-22-0237] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 06/16/2022] [Accepted: 08/31/2022] [Indexed: 01/07/2023]
Abstract
Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces the metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active human subject plasma demonstrated increased carbohydrate utilization following exercise. Epidemiologic data from a 20-year prospective study of a large human cohort of initially cancer-free participants revealed that exercise prior to cancer initiation had a modest impact on cancer incidence in low metastatic stages but significantly reduced the likelihood of highly metastatic cancer. In three models of melanoma in mice, exercise prior to cancer injection significantly protected against metastases in distant organs. The protective effects of exercise were dependent on mTOR activity, and inhibition of the mTOR pathway with rapamycin treatment ex vivo reversed the exercise-induced metabolic shield. Under limited glucose conditions, active stroma consumed significantly more glucose at the expense of the tumor. Collectively, these data suggest a clash between the metabolic plasticity of cancer and exercise-induced metabolic reprogramming of the stroma, raising an opportunity to block metastasis by challenging the metabolic needs of the tumor. SIGNIFICANCE Exercise protects against cancer progression and metastasis by inducing a high nutrient demand in internal organs, indicating that reducing nutrient availability to tumor cells represents a potential strategy to prevent metastasis. See related commentary by Zerhouni and Piskounova, p. 4124.
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Affiliation(s)
- Danna Sheinboim
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shivang Parikh
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Paulee Manich
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Irit Markus
- Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, and Sylvan Adams Sports Institute, Tel Aviv University, Tel Aviv, Israel
| | - Sapir Dahan
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Roma Parikh
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Elisa Stubbs
- Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, and Sylvan Adams Sports Institute, Tel Aviv University, Tel Aviv, Israel
| | - Gali Cohen
- Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, and Sylvan Adams Sports Institute, Tel Aviv University, Tel Aviv, Israel.,Stanley Steyer Institute for Cancer Epidemiology and Research, Tel Aviv University, Tel Aviv, Israel
| | | | - Rachel E. Bell
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sara Arciniegas Ruiz
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ruth Percik
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Endocrinology, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Ronen Brenner
- Institute of Oncology, E. Wolfson Medical Center, Holon, Israel
| | - Stav Leibou
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Hananya Vaknine
- Institute of Pathology, E. Wolfson Medical Center, Holon, Israel
| | - Gali Arad
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yariv Gerber
- Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, and Sylvan Adams Sports Institute, Tel Aviv University, Tel Aviv, Israel.,Stanley Steyer Institute for Cancer Epidemiology and Research, Tel Aviv University, Tel Aviv, Israel
| | - Lital Keinan-Boker
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel.,Israel Center for Disease Control, Israel Ministry of Health, Ramat Gan, Israel
| | - Tal Shimony
- Israel Center for Disease Control, Israel Ministry of Health, Ramat Gan, Israel
| | - Lior Bikovski
- The Myers Neuro-Behavioral Core Facility, Tel Aviv University, Tel Aviv, Israel.,School of Behavioral Sciences, Netanya Academic College, Netanya, Israel
| | - Nir Goldstein
- Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, and Sylvan Adams Sports Institute, Tel Aviv University, Tel Aviv, Israel
| | - Keren Constantini
- Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, and Sylvan Adams Sports Institute, Tel Aviv University, Tel Aviv, Israel
| | - Sapir Labes
- Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Shimonov Mordechai
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Surgery, E. Wolfson Medical Center, Holon, Israel
| | - Hila Doron
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ariel Lonescu
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tamar Ziv
- The Smoler Proteomics Center, Technion, Haifa, Israel
| | - Eran Nizri
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Dermatology, Tel Aviv Sourasky (Ichilov) Medical Center, Tel Aviv, Israel
| | - Guy Choshen
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Internal Medicine, Tel Aviv Sourasky (Ichilov) Medical Center, Tel Aviv, Israel
| | - Hagit Eldar-Finkelman
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yuval Tabach
- Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Aharon Helman
- Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel
| | - Shamgar Ben-Eliyahu
- School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel.,Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Neta Erez
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eran Perlson
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Tamar Geiger
- The Weizmann Institute of Science, Rehovot, Israel
| | - Danny Ben-Zvi
- Department of Developmental Biology and Cancer Research, Institute of Medical Research Israel–Canada, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Mehdi Khaled
- INSERM 1186, Gustave Roussy, Université Paris-Saclay, Villejuif, France.,Corresponding Authors: Carmit Levy, Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, 69978, Israel. E-mail: ; Yftach Gepner, E-mail: ; and Mehdi Khaled, E-mail:
| | - Yftach Gepner
- Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, and Sylvan Adams Sports Institute, Tel Aviv University, Tel Aviv, Israel.,Corresponding Authors: Carmit Levy, Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, 69978, Israel. E-mail: ; Yftach Gepner, E-mail: ; and Mehdi Khaled, E-mail:
| | - Carmit Levy
- Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Corresponding Authors: Carmit Levy, Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, 69978, Israel. E-mail: ; Yftach Gepner, E-mail: ; and Mehdi Khaled, E-mail:
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9
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Pardridge WM. A Historical Review of Brain Drug Delivery. Pharmaceutics 2022; 14:1283. [PMID: 35745855 PMCID: PMC9229021 DOI: 10.3390/pharmaceutics14061283] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/01/2022] [Accepted: 06/07/2022] [Indexed: 12/13/2022] Open
Abstract
The history of brain drug delivery is reviewed beginning with the first demonstration, in 1914, that a drug for syphilis, salvarsan, did not enter the brain, due to the presence of a blood-brain barrier (BBB). Owing to restricted transport across the BBB, FDA-approved drugs for the CNS have been generally limited to lipid-soluble small molecules. Drugs that do not cross the BBB can be re-engineered for transport on endogenous BBB carrier-mediated transport and receptor-mediated transport systems, which were identified during the 1970s-1980s. By the 1990s, a multitude of brain drug delivery technologies emerged, including trans-cranial delivery, CSF delivery, BBB disruption, lipid carriers, prodrugs, stem cells, exosomes, nanoparticles, gene therapy, and biologics. The advantages and limitations of each of these brain drug delivery technologies are critically reviewed.
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Affiliation(s)
- William M Pardridge
- Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
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10
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Martina SJ, Lelo A, Lindarto D, Ganie RA, Ichwan M, Yusuf H, Ilyas S, Nasution IP. The Effect of Coffee Arabica Gayo Leaf Extract (Coffea arabica L.) in Increasing Phosphoinositide 3-kinase and Glucose Transporter-4 Expression in the Skeletal Muscle. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.5985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Diabetes mellitus (DM) is a chronic and progressive metabolic disease characterized by hyperglycemia due to impaired insulin secretion associated with a lack of phosphoinositide 3-kinase (PI3K) and glucose transporter-4 (GLUT-4) expression in the skeletal muscle membrane.
AIM: The aim of the study is to understand the effect of coffee Arabica Gayo leaf extract (Coffea arabica L.) in increasing PI3K expression and GLUT-4 expression in the skeletal muscle membrane.
METHODS: Thirty-five male Wistar rats with Type 2 DM (T2DM) induced using a combination of a high-fat diet for 5 weeks followed by multiple intraperitoneal injections of low-dose streptozotocin (30 mg/kg). Divided into seven groups as such two groups that did not receive treatment and five groups that received treatment. The dosage administered was 150, 200, and 250 mg/kg/day through the nasogastric tube for 30 days. PI3K and GLUT-4 expression in the skeletal muscle membrane was evaluated by Immunohistochemistry in their gastrocnemius muscles.
RESULTS: The study showed an increased expression of PI3K and GLUT-4 expression. There was a significant difference between coffee Arabica Gayo leaf extract and Metformin in increasing GLUT-4 expression (p = 0.036) and PI3K expression between coffee Arabica Gayo dose 250 mg/kg/day and group without treatment (p = 0.008).
CONCLUSION: Coffee Arabica Gayo leaf extract (C. arabica L) at a dose of 250 mg/kg/day can increase PI3K expression in skeletal muscle and a dose of 200 mg/kg/day and 250 mg/kg/day can increase the expression of GLUT-4 in the skeletal muscle membrane greater than metformin.
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11
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Behl T, Sehgal A, Grover M, Singh S, Sharma N, Bhatia S, Al-Harrasi A, Aleya L, Bungau S. Uncurtaining the pivotal role of ABC transporters in diabetes mellitus. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:41533-41551. [PMID: 34085197 DOI: 10.1007/s11356-021-14675-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 05/27/2021] [Indexed: 06/12/2023]
Abstract
The metabolic disorders are the edge points for the initiation of various diseases. These disorders comprised of several diseases including diabetes, obesity, and cardiovascular complications. Worldwide, the prevalence of these disorders is increasing day by day. The world's population is at higher threat of developing metabolic disease, especially diabetes. Therefore, there is an impregnable necessity of searching for a newer therapeutic target to reduce the burden of these disorders. Diabetes mellitus (DM) is marked with the dysregulated insulin secretion and resistance. The lipid and glucose transporters portray a pivotal role in the metabolism and transport of both of these. The excess production of lipid and glucose and decreased clearance of these leads to the emergence of DM. The ATP-binding cassette transporters (ABCT) are important for the metabolism of glucose and lipid. Various studies suggest the key involvement of ABCT in the pathologic process of different diseases. In addition, the involvement of other pathways, including IGF signaling, P13-Akt/PKC/MAPK signaling, and GLP-1 via regulation of ABCT, may help develop new treatment strategies to cope with insulin resistance dysregulated glucose metabolism, key features in DM.
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Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Madhuri Grover
- BS Anangpuria Institute of Pharmacy, Faridabad, Haryana, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Saurabh Bhatia
- Amity Institute of Pharmacy, Amity University, Gurugram, Haryana, India
- Natural & Medical Sciences Research Centre, University of Nizwa, Birkat Al Mauz, Nizwa, Oman
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Centre, University of Nizwa, Birkat Al Mauz, Nizwa, Oman
| | - Lotfi Aleya
- Chrono-Environment Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, Besançon, France
| | - Simona Bungau
- Department of Pharmacy, Faculty of Pharmacy, University of Oradea, Oradea, Romania
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12
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Nahrjou N, Ghosh A, Tanasova M. Targeting of GLUT5 for Transporter-Mediated Drug-Delivery Is Contingent upon Substrate Hydrophilicity. Int J Mol Sci 2021; 22:ijms22105073. [PMID: 34064801 PMCID: PMC8150966 DOI: 10.3390/ijms22105073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/28/2021] [Accepted: 05/08/2021] [Indexed: 12/14/2022] Open
Abstract
Specific link between high fructose uptake and cancer development and progression highlighted fructose transporters as potential means to achieve GLUT-mediated discrimination between normal and cancer cells. The gained expression of fructose-specific transporter GLUT5 in various cancers offers a possibility for developing cancer-specific imaging and bioactive agents. Herein, we explore the feasibility of delivering a bioactive agent through cancer-relevant fructose-specific transporter GLUT5. We employed specific targeting of GLUT5 by 2,5-anhydro-D-mannitol and investigated several drug conjugates for their ability to induce cancer-specific cytotoxicity. The proof-of-concept analysis was carried out for conjugates of chlorambucil (CLB) in GLUT5-positive breast cancer cells and normal breast cells. The cytotoxicity of conjugates was assessed over 24 h and 48 h, and significant dependence between cancer-selectivity and conjugate size was observed. The differences were found to relate to the loss of GLUT5-mediated uptake upon increased conjugate size and hydrophobicity. The findings provide information on the substrate tolerance of GLUT5 and highlight the importance of maintaining appropriate hydrophilicity for GLUT-mediated delivery.
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Affiliation(s)
- Nazanin Nahrjou
- Chemistry Department, Michigan Technological University, Houghton, MI 49931, USA; (N.N.); (A.G.)
| | - Avik Ghosh
- Chemistry Department, Michigan Technological University, Houghton, MI 49931, USA; (N.N.); (A.G.)
| | - Marina Tanasova
- Chemistry Department, Michigan Technological University, Houghton, MI 49931, USA; (N.N.); (A.G.)
- Health Research Institute, Michigan Technological University, Houghton, MI 49931, USA
- Correspondence:
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13
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Viegas FO, Neuhauss SCF. A Metabolic Landscape for Maintaining Retina Integrity and Function. Front Mol Neurosci 2021; 14:656000. [PMID: 33935647 PMCID: PMC8081888 DOI: 10.3389/fnmol.2021.656000] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/22/2021] [Indexed: 01/27/2023] Open
Abstract
Neurons have high metabolic demands that are almost exclusively met by glucose supplied from the bloodstream. Glucose is utilized in complex metabolic interactions between neurons and glia cells, described by the astrocyte-neuron lactate shuttle (ANLS) hypothesis. The neural retina faces similar energy demands to the rest of the brain, with additional high anabolic needs to support continuous renewal of photoreceptor outer segments. This demand is met by a fascinating variation of the ANLS in which photoreceptors are the central part of a metabolic landscape, using glucose and supplying surrounding cells with metabolic intermediates. In this review we summarize recent evidence on how neurons, in particular photoreceptors, meet their energy and biosynthetic requirements by comprising a metabolic landscape of interdependent cells.
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Affiliation(s)
- Filipe O Viegas
- Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.,Life Science Zurich Graduate School, Ph.D. Program in Molecular Life Sciences, Zurich, Switzerland
| | - Stephan C F Neuhauss
- Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
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14
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Tilekar K, Upadhyay N, Iancu CV, Pokrovsky V, Choe JY, Ramaa CS. Power of two: combination of therapeutic approaches involving glucose transporter (GLUT) inhibitors to combat cancer. Biochim Biophys Acta Rev Cancer 2020; 1874:188457. [PMID: 33096154 PMCID: PMC7704680 DOI: 10.1016/j.bbcan.2020.188457] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/16/2020] [Accepted: 10/16/2020] [Indexed: 12/20/2022]
Abstract
Cancer research of the Warburg effect, a hallmark metabolic alteration in tumors, focused attention on glucose metabolism whose targeting uncovered several agents with promising anticancer effects at the preclinical level. These agents' monotherapy points to their potential as adjuvant combination therapy to existing standard chemotherapy in human trials. Accordingly, several studies on combining glucose transporter (GLUT) inhibitors with chemotherapeutic agents, such as doxorubicin, paclitaxel, and cytarabine, showed synergistic or additive anticancer effects, reduced chemo-, radio-, and immuno-resistance, and reduced toxicity due to lowering the therapeutic doses required for desired chemotherapeutic effects, as compared with monotherapy. The combinations have been specifically effective in treating cancer glycolytic phenotypes, such as pancreatic and breast cancers. Even combining GLUT inhibitors with other glycolytic inhibitors and energy restriction mimetics seems worthwhile. Though combination clinical trials are in the early phase, initial results are intriguing. The various types of GLUTs, their role in cancer progression, GLUT inhibitors, and their anticancer mechanism of action have been reviewed several times. However, utilizing GLUT inhibitors as combination therapeutics has received little attention. We consider GLUT inhibitors agents that directly affect glucose transporters by binding to them or indirectly alter glucose transport by changing the transporters' expression level. This review mainly focuses on summarizing the effects of various combinations of GLUT inhibitors with other anticancer agents and providing a perspective on the current status.
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Affiliation(s)
- Kalpana Tilekar
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India
| | - Neha Upadhyay
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India
| | - Cristina V. Iancu
- East Carolina Diabetes and Obesity Institute, Department of Chemistry, East Carolina University, Greenville, North Carolina, USA
| | - Vadim Pokrovsky
- Laboratory of Combined Therapy, N.N. Blokhin Cancer Research Center, Moscow, Russia
- Department of Biochemistry, People’s Friendship University, Moscow, Russia
| | - Jun-yong Choe
- East Carolina Diabetes and Obesity Institute, Department of Chemistry, East Carolina University, Greenville, North Carolina, USA
| | - C. S. Ramaa
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India
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15
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Wang T, Wang J, Hu X, Huang XJ, Chen GX. Current understanding of glucose transporter 4 expression and functional mechanisms. World J Biol Chem 2020; 11:76-98. [PMID: 33274014 PMCID: PMC7672939 DOI: 10.4331/wjbc.v11.i3.76] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/22/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
Glucose is used aerobically and anaerobically to generate energy for cells. Glucose transporters (GLUTs) are transmembrane proteins that transport glucose across the cell membrane. Insulin promotes glucose utilization in part through promoting glucose entry into the skeletal and adipose tissues. This has been thought to be achieved through insulin-induced GLUT4 translocation from intracellular compartments to the cell membrane, which increases the overall rate of glucose flux into a cell. The insulin-induced GLUT4 translocation has been investigated extensively. Recently, significant progress has been made in our understanding of GLUT4 expression and translocation. Here, we summarized the methods and reagents used to determine the expression levels of Slc2a4 mRNA and GLUT4 protein, and GLUT4 translocation in the skeletal muscle, adipose tissues, heart and brain. Overall, a variety of methods such real-time polymerase chain reaction, immunohistochemistry, fluorescence microscopy, fusion proteins, stable cell line and transgenic animals have been used to answer particular questions related to GLUT4 system and insulin action. It seems that insulin-induced GLUT4 translocation can be observed in the heart and brain in addition to the skeletal muscle and adipocytes. Hormones other than insulin can induce GLUT4 translocation. Clearly, more studies of GLUT4 are warranted in the future to advance of our understanding of glucose homeostasis.
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Affiliation(s)
- Tiannan Wang
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
| | - Jing Wang
- College of Pharmacy, South-Central University for Nationalities, Wuhan 430074, Hubei Province, China
| | - Xinge Hu
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
| | - Xian-Ju Huang
- College of Pharmacy, South-Central University for Nationalities, Wuhan 430074, Hubei Province, China
| | - Guo-Xun Chen
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
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16
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Delling C, Daugschies A, Bangoura B, Dengler F. Cryptosporidium parvum alters glucose transport mechanisms in infected enterocytes. Parasitol Res 2019; 118:3429-3441. [PMID: 31667591 DOI: 10.1007/s00436-019-06471-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 09/24/2019] [Indexed: 11/25/2022]
Abstract
The parasite Cryptosporidium parvum Tyzzer 1912 destroys parts of the intestinal brush border membrane which is important for the uptake of nutrients like glucose. In this study, glucose transport mechanisms of the host cells (IPEC-J2 cells) infected by C. parvum were investigated. The mRNA expression levels of glucose transporters (GLUT) 1 and 2 and Na+-coupled glucose transporter (SGLT) 1 were compared in infected and uninfected cells over an infection time of 24-96 h by RT-qPCR. Furthermore, the protein expression of SGLT 1 and GLUT 2 was quantified in western blot studies. While the protein expression of SGLT 1 was not altered in infected cells, mRNA expression of SGLT 1 and GLUT 1 was significantly increased 24 h p. i. and decreased 96 h p. i. The mRNA expression of GLUT 2 was significantly decreased 24 h, 72 h, and 96 h p. i. and also correlated significantly with the infection dose at 72 h p. i. In contrast to that, the protein expression of GLUT 2 was significantly increased 48 h p. i., associated with a significantly higher intracellular glucose level in infected cells compared with control cells at that time point of infection. This points to an adaptation of the host cells' glucose uptake taking place in the acute phase of the infection. A better understanding of these molecular mechanisms following a C. parvum infection may probably lead to an improvement of therapy strategies in the future.
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Affiliation(s)
- Cora Delling
- Institute of Parasitology, Faculty of Veterinary Medicine, University of Leipzig, An den Tierkliniken 35, 04103, Leipzig, Germany.
| | - Arwid Daugschies
- Institute of Parasitology, Faculty of Veterinary Medicine, University of Leipzig, An den Tierkliniken 35, 04103, Leipzig, Germany
- Albrecht Daniel Thaer Institute, An den Tierkliniken 29, 04103, Leipzig, Germany
| | - Berit Bangoura
- Wyoming State Veterinary Laboratory, Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY, 82070, USA
| | - Franziska Dengler
- Institute of Veterinary Physiology, Faculty of Veterinary Medicine, University of Leipzig, An den Tierkliniken 7, 04103, Leipzig, Germany
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17
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Morrin ST, Owens RA, Le Berre M, Gerlach JQ, Joshi L, Bode L, Irwin JA, Hickey RM. Interrogation of Milk-Driven Changes to the Proteome of Intestinal Epithelial Cells by Integrated Proteomics and Glycomics. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:1902-1917. [PMID: 30663306 DOI: 10.1021/acs.jafc.8b06484] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Bovine colostrum is a rich source of bioactive components which are important in the development of the intestine, in stimulating gut structure and function and in preparing the gut surface for subsequent colonization of microbes. What is not clear, however, is how colostrum may affect the repertoire of receptors and membrane proteins of the intestinal surface and the post-translational modifications associated with them. In the present work, we aimed to characterize the surface receptor and glycan profile of human HT-29 intestinal cells after exposure to a bovine colostrum fraction (BCF) by means of proteomic and glycomic analyses. Integration of label-free quantitative proteomic analysis and lectin array profiles confirmed that BCF exposure results in changes in the levels of glycoproteins present at the cell surface and also changes to their glycosylation pattern. This study contributes to our understanding of how milk components may regulate intestinal cells and prime them for bacterial interaction.
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Affiliation(s)
- Sinead T Morrin
- Teagasc Food Research Centre , Moorepark , Fermoy, P61C996 , County Cork , Ireland
- Veterinary Sciences Centre, School of Veterinary Medicine , University College Dublin , Belfield, Dublin 4, D04 V1W8 , Ireland
| | - Rebecca A Owens
- Department of Biology , Maynooth University , Maynooth , W23 F2H6 , County Kildare , Ireland
| | - Marie Le Berre
- Glycoscience Group, Advanced Glycoscience Research Cluster, National Centre for Biomedical Engineering Science , National University of Ireland Galway , H91TK33 , Galway , Ireland
| | - Jared Q Gerlach
- Glycoscience Group, Advanced Glycoscience Research Cluster, National Centre for Biomedical Engineering Science , National University of Ireland Galway , H91TK33 , Galway , Ireland
| | - Lokesh Joshi
- Glycoscience Group, Advanced Glycoscience Research Cluster, National Centre for Biomedical Engineering Science , National University of Ireland Galway , H91TK33 , Galway , Ireland
| | - Lars Bode
- Department of Pediatrics and Larsson-Rosenquist Foundation Mother-Milk-Infant Center of Research Excellence , University of California, San Diego , La Jolla , California 92093 , United States
| | - Jane A Irwin
- Veterinary Sciences Centre, School of Veterinary Medicine , University College Dublin , Belfield, Dublin 4, D04 V1W8 , Ireland
| | - Rita M Hickey
- Teagasc Food Research Centre , Moorepark , Fermoy, P61C996 , County Cork , Ireland
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18
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Liu G, Ma C, Jin BK, Chen Z, Cheng FL, Zhu JJ. Electrochemiluminescence Investigation of Glucose Transporter 4 Expression at Skeletal Muscle Cells Surface Based on a Graphene Hydrogel Electrode. Anal Chem 2019; 91:3021-3026. [PMID: 30693766 DOI: 10.1021/acs.analchem.8b05340] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
In situ detection of the expression level of cell-surface receptors has become a hotspot study in recent years. We propose in this manuscript a novel strategy for sensitive electrochemiluminescence (ECL) detection of glucose transporter 4 (GLUT4) on human skeletal muscle cells (HSMCs). Graphene hydrogel (GH) was selected to fabricate a permeable electrode with the purpose of overcoming the steric hindrance of cells on electrode, which leads to errors in the detection of cell-surface receptors. GLUT4 was labeled with carbon dots (CDs), which generate ECL emission at the interface between GH and cells, so about half the amount of GLUT4 expressed at the cell surface could be determined, which provided an accurate GLUT4 expression quantification. The prepared cytosensor exhibited good analytical performance for HSMC cells, ranging from 500 to 1.0 × 106 cells·mL-1, with a detection limit of 200 cells·mL-1. The average amount of GLUT4 per HSMC cell was calculated to be 1.88 × 105. Furthermore, GLUT4 on HSMC surface had a 2.3-fold increase under the action of insulin. This strategy is capable of evaluating the receptors on the cell surface, which may push the application of ECL for disease diagnosis.
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Affiliation(s)
- Gen Liu
- College of Chemistry & Chemical Engineering , Anhui University , Hefei 230601 , P. R. China.,State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering , Nanjing University , Nanjing 210023 , P. R. China
| | - Cheng Ma
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering , Nanjing University , Nanjing 210023 , P. R. China
| | - Bao-Kang Jin
- College of Chemistry & Chemical Engineering , Anhui University , Hefei 230601 , P. R. China
| | - Zixuan Chen
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering , Nanjing University , Nanjing 210023 , P. R. China
| | - Fa-Liang Cheng
- Guangdong Engineering and Technology Research Center for Advanced Nanomaterials, School of Environment and Civil Engineering , Dongguan University of Technology , Dongguan 523808 , P. R. China
| | - Jun-Jie Zhu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering , Nanjing University , Nanjing 210023 , P. R. China
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19
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Abstract
Xenopus laevis oocytes are a useful heterologous expression system for expressing glucose transporters (GLUTs) and examining their functions. In this chapter, we provide a detailed protocol on oocyte extraction and preparation for GLUT9 protein expression. Furthermore, we describe the determination of GLUT9 overexpression level by biotinylation and Western blotting analysis. Finally, we also describe how GLUT9-expressing oocytes can be used to measure urate kinetics by radioisotopes as well as two-microelectrode voltage clamping techniques.
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20
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Al-Ahmad AJ. Comparative study of expression and activity of glucose transporters between stem cell-derived brain microvascular endothelial cells and hCMEC/D3 cells. Am J Physiol Cell Physiol 2017; 313:C421-C429. [PMID: 28993322 DOI: 10.1152/ajpcell.00116.2017] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 07/28/2017] [Accepted: 07/28/2017] [Indexed: 12/22/2022]
Abstract
Glucose constitutes a major source of energy of mammalian brains. Glucose uptake at the blood-brain barrier (BBB) occurs through a facilitated glucose transport, through glucose transporter 1 (GLUT1), although other isoforms have been described at the BBB. Mutations in GLUT1 are associated with the GLUT1 deficiency syndrome, yet none of the current in vitro models of the human BBB maybe suited for modeling such a disorder. In this study, we investigated the expression of glucose transporters and glucose diffusion across brain microvascular endothelial cells (BMECs) derived from healthy patient-derived induced pluripotent stem cells (iPSCs). We investigated the expression of different glucose transporters at the BBB using immunocytochemistry and flow cytometry and measured glucose uptake and diffusion across BMEC monolayers obtained from two iPSC lines and from hCMEC/D3 cells. BMEC monolayers showed expression of several glucose transporters, in particular GLUT1, GLUT3, and GLUT4. Diffusion of glucose across the monolayers was mediated via a saturable transcellular mechanism and partially inhibited by pharmacological inhibitors. Taken together, our study suggests the presence of several glucose transporters isoforms at the human BBB and demonstrates the feasibility of modeling glucose across the BBB using patient-derived stem cells.
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Affiliation(s)
- Abraham J Al-Ahmad
- Texas Tech University Health Sciences Center, School of Pharmacy, Department of Pharmaceutical Sciences, Amarillo, Texas
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