Therapeutic implications of glucose transporters (GLUT) in cerebral ischemia

Sharma, Veerta; Singh, Thakur Gurjeet; Mannan, Ashi

doi:10.1007/s11064-022-03620-1

Cited by 12 publications

(8 citation statements)

References 66 publications

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“…Among them, GLUT1, GLUT2 (SLC2A2), GLUT3 (SLC2A3), and GLUT4 (SLC2A4) are the four most well-known subtypes, which have distinct regulatory mechanisms and kinetic characteristic and each subtype plays a specific function in maintaining cellular and organismal glucose homeostasis [ 29 , 30 ]. GLUT1 is a widely distributed glucose transporter whose expression is regulated by hypoxia-inducible factor-1α (HIF-1α) [ 31 , 32 ]. GLUT1 has a high affinity for glucose and is highly expressed in a variety of cancers, including lung cancer, prostate cancer, kidney cancer, and lymphoma [ 33 ].…”

Section: Drugs That Target Glucose Metabolism Enzymesmentioning

confidence: 99%

Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies

Zhang

Huang

et al. 2022

Cancers

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Reprogramming of glucose metabolism provides sufficient energy and raw materials for the proliferation, metastasis, and immune escape of cancer cells, which is enabled by glucose metabolism-related enzymes that are abundantly expressed in a broad range of cancers. Therefore, targeting glucose metabolism enzymes has emerged as a promising strategy for anticancer drug development. Although several glucose metabolism modulators have been approved for cancer treatment in recent years, some limitations exist, such as a short half-life, poor solubility, and numerous adverse effects. With the rapid development of medicinal chemicals, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Additionally, several studies have found that some natural products can suppress cancer progression by regulating glucose metabolism enzymes. In this review, we summarize the mechanisms underlying the reprogramming of glucose metabolism and present enzymes that could serve as therapeutic targets. In addition, we systematically review the existing drugs targeting glucose metabolism enzymes, including small-molecule modulators and natural products. Finally, the opportunities and challenges for glucose metabolism enzyme-targeted anticancer drugs are also discussed. In conclusion, combining glucose metabolism modulators with conventional anticancer drugs may be a promising cancer treatment strategy.

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Section: Drugs That Target Glucose Metabolism Enzymesmentioning

confidence: 99%

Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies

Zhang

Huang

et al. 2022

Cancers

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“…After cerebral ischemia, the upregulation of GLUT1, a key protein for glucose transport, represents this adaptive shift. 22 , 23 The inhibition of GLUTs function led to abnormal brain function and neuronal death, and the upregulation of GLUT1 and GLUT3 demonstrated neuroprotective effect on cerebral ischemia. 23 PFKFB3, the target of HIF1α, is a critical regulatory molecule in glycolysis control and has high kinase activity.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Adenovirus-Mediated HIF-lα Ameliorates Neurological Dysfunction by Improving Energy Metabolism in Ischemic Penumbra After Cerebral Ischemia-Reperfusion in Rats

Zhou¹,

Tao²,

Yu³

et al. 2023

NDT

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Background Hypoxia inducible factor-1α (HIF-1α) regulates glucose metabolism during ischemia. This study investigated the effect of recombinant adenovirus HIF-1ɑ on neurological function and energy metabolism in a rat cerebral ischemia-reperfusion model. Methods Rats were divided into four groups: sham-operated (Sham) group, cerebral ischemia-reperfusion (CIR) group, recombinant adenovirus empty vector (Ad) group, and recombinant adenovirus-mediated HIF-1α (AdHIF-1α) group. The AdHIF-1α group and the Ad group were injected with AdHIF-1α and Ad in the lateral ventricle. The mNSS was performed at post-ischemia day 0 (P0) and P1, P14 and P28. At P14, the cerebral infarct volume was compared. At P28, HE staining, Nissl stains and TUNEL staining were performed. The expression of HIF-1α, GLUT1 and PFKFB3 were evaluated by Western Blot and immunohistochemistry. High performance liquid chromatography (HPLC) was used to determine the expression of GLUT1 and PFKFB3, and the level of energy metabolites: ATP, ADP and AMP. Results mNSS scores in the AdHIF-1α group were consistently lower than those in the CIR and Ad groups from P14 (P < 0.05) and Ad groups (P < 0.05). The cerebral infarct volume was reduced in the AdHIF-1α group compared with that in CIR group and Ad group (P < 0.05). At P28, HE showed better pathological changes in AdHIF-1α group. The number of Nissl bodies was increased in the AdHIF-1α group compared with the CIR and Ad groups (P < 0.05). The number of apoptotic cells in the AdHIF-1α group was fewer than that in the CIR and Ad groups (P < 0.05). The expression of HIF-1α, GLUT1 and PFKFB3 was significantly higher in the AdHIF-1α group compared with the CIR and Ad groups (P < 0.05). The ATP, ADP and AMP in the ischemic penumbra were also higher in the AdHIF-1α group (P < 0.05). Conclusion HIF-lα promoted neurological function recovery and decreased cerebral infarct volume in rats after cerebral ischemia-reperfusion injury by improving energy metabolism.

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“…Chronic hyperglycaemia results in an adaptative decrease in 55 kD GLUT1 density on the BBB, which reduces glucose transport into the brain [ 21 , 22 , 23 ]. In turn, in chronic hypoglycaemia, hypoxia and several acquired and congenital metabolic diseases, the density of 55 kD GLUT1 increases, adjusting in part the rate of inward transport of glucose to these conditions [ 24 , 25 ]. Upregulation of GLUT1 is mediated by the phosphatidylinositol-3-kinase, AMP-activated protein kinase, cAMP response element–binding protein and hypoxia inducible factor pathways.…”

Section: Glucose and Lactate—the Key Precursors Of Brain Acetyl-coa I...mentioning

confidence: 99%

“…Upregulation of GLUT1 is mediated by the phosphatidylinositol-3-kinase, AMP-activated protein kinase, cAMP response element–binding protein and hypoxia inducible factor pathways. On the other hand, the mitogen-activated protein kinase pathway downregulates GLUT 1 and 3 expression [ 25 ]. Such mechanisms tend to reduce concentration-dependent fluctuations in the rate of glucose transport into the brain.…”

Section: Glucose and Lactate—the Key Precursors Of Brain Acetyl-coa I...mentioning

confidence: 99%

“…Under normal conditions, BHB concentration in the blood is in the range of 0.05 mmol/L, which excludes its effective transport into the brain. Pyruvate at similar concentrations is transported five times faster due to ten times higher affinity to MCT2 [ 25 ]. However, during starvation, stressful conditions, high-fat diet, diabetic ketoacidosis or hypoxia, BHB is synthesised and released from the liver in marked amounts that may reach blood concentrations as high as 5–20 mmol/L.…”

Section: Fatty Acids and Ketone Bodies In Brain Acetyl-coa Metabolismmentioning

confidence: 99%

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Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain

Jankowska-Kulawy

Klimaszewska-Łata

Gul-Hinc

et al. 2022

IJMS

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The human brain is characterised by the most diverse morphological, metabolic and functional structure among all body tissues. This is due to the existence of diverse neurons secreting various neurotransmitters and mutually modulating their own activity through thousands of pre- and postsynaptic interconnections in each neuron. Astroglial, microglial and oligodendroglial cells and neurons reciprocally regulate the metabolism of key energy substrates, thereby exerting several neuroprotective, neurotoxic and regulatory effects on neuronal viability and neurotransmitter functions. Maintenance of the pool of mitochondrial acetyl-CoA derived from glycolytic glucose metabolism is a key factor for neuronal survival. Thus, acetyl-CoA is regarded as a direct energy precursor through the TCA cycle and respiratory chain, thereby affecting brain cell viability. It is also used for hundreds of acetylation reactions, including N-acetyl aspartate synthesis in neuronal mitochondria, acetylcholine synthesis in cholinergic neurons, as well as divergent acetylations of several proteins, peptides, histones and low-molecular-weight species in all cellular compartments. Therefore, acetyl-CoA should be considered as the central point of metabolism maintaining equilibrium between anabolic and catabolic pathways in the brain. This review presents data supporting this thesis.

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Therapeutic implications of glucose transporters (GLUT) in cerebral ischemia

Cited by 12 publications

References 66 publications

Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies

Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies

Recombinant Adenovirus-Mediated HIF-lα Ameliorates Neurological Dysfunction by Improving Energy Metabolism in Ischemic Penumbra After Cerebral Ischemia-Reperfusion in Rats

Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain

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