The Experts below are selected from a list of 10287 Experts worldwide ranked by ideXlab platform
Marcus E Raichle - One of the best experts on this subject based on the ideXlab platform.
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Aerobic Glycolysis and tau deposition in preclinical alzheimer s disease
Neurobiology of Aging, 2018Co-Authors: Andrei G Vlassenko, Manu S Goyal, Tyler Blazey, Lars E Couture, Tony J Durbin, John C Morris, Brian A Gordon, Jon Christensen, Hussain Jafri, Marcus E RaichleAbstract:Abstract Research of the human brain metabolism in vivo has largely focused on total glucose use (via fluorodeoxyglucose positron emission tomography) and, until recently, did not examine the use of glucose outside oxidative phosphorylation, which is known as Aerobic Glycolysis (AG). AG supports important functions including biosynthesis and neuroprotection but decreases dramatically with aging. This multitracer positron emission tomography study evaluated the relationship between AG, total glucose use (CMRGlc), oxygen metabolism (CMRO2), tau, and amyloid deposition in 42 individuals, including those at preclinical and symptomatic stages of Alzheimer's disease. Our findings demonstrate that in individuals with amyloid burden, lower AG is associated with higher tau deposition. No such correlation was observed for CMRGlc or CMRO2. We suggest that aging-related loss of AG leading to decreased synaptic plasticity and neuroprotection may accelerate tauopathy in individuals with amyloid burden. Longitudinal AG and Alzheimer's disease pathology studies are needed to verify causality.
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loss of brain Aerobic Glycolysis in normal human aging
Cell Metabolism, 2017Co-Authors: Manu S Goyal, Andrei G Vlassenko, Tyler Blazey, Yi Su, Lars E Couture, Tony J Durbin, Randall J Bateman, Tammie L S Benzinger, John C Morris, Marcus E RaichleAbstract:Summary The normal aging human brain experiences global decreases in metabolism, but whether this affects the topography of brain metabolism is unknown. Here we describe PET-based measurements of brain glucose uptake, oxygen utilization, and blood flow in cognitively normal adults from 20 to 82 years of age. Age-related decreases in brain glucose uptake exceed that of oxygen use, resulting in loss of brain Aerobic Glycolysis (AG). Whereas the topographies of total brain glucose uptake, oxygen utilization, and blood flow remain largely stable with age, brain AG topography changes significantly. Brain regions with high AG in young adults show the greatest change, as do regions with prolonged developmental transcriptional features (i.e., neoteny). The normal aging human brain thus undergoes characteristic metabolic changes, largely driven by global loss and topographic changes in brain AG.
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brain Aerobic Glycolysis and motor adaptation learning
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Benjamin J Shannon, Andrei G Vlassenko, Sanjeev N Vaishnavi, Joshua S Shimony, Jerrel Rutlin, Marcus E RaichleAbstract:Ten percent to 15% of glucose used by the brain is metabolized nonoxidatively despite adequate tissue oxygenation, a process termed Aerobic Glycolysis (AG). Because of the known role of Glycolysis in biosynthesis, we tested whether learning-induced synaptic plasticity would lead to regionally appropriate, learning-dependent changes in AG. Functional MRI (fMRI) before, during, and after performance of a visual–motor adaptation task demonstrated that left Brodmann area 44 (BA44) played a key role in adaptation, with learning-related changes to activity during the task and altered resting-state, functional connectivity after the task. PET scans before and after task performance indicated a sustained increase in AG in left BA 44 accompanied by decreased oxygen consumption. Intersubject variability in behavioral adaptation rate correlated strongly with changes in AG in this region, as well as functional connectivity, which is consistent with a role for AG in synaptic plasticity.
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brain Aerobic Glycolysis functions and alzheimer s disease
Clinical and Translational Imaging, 2015Co-Authors: Andrei G Vlassenko, Marcus E RaichleAbstract:Genetic, biochemical, pathological, and biomarker data demonstrate that Alzheimer's disease (AD) pathology, including the initiation and progressive buildup of insoluble forms of beta-amyloid (Aβ), appears to begin ~ 10-15 years prior to the onset of cognitive decline associated with AD. Metabolic dysfunction, a prominent feature of the evolving brain pathology, is reflected in a decline of total glucose utilization. Despite decades of interest in declining glucose use in AD no detailed consideration had been given to the possibility that this decline is not just a decline in energy consumption but rather in Glycolysis alone. Glycolysis is a multi-step process that prepares the glucose molecule for oxidative phosphorylation and the generation of energy. In the normal brain, Glycolysis exceeds that required for the needs of oxidative phosphorylation. Because it is occurring in a setting with adequate oxygen available for oxidative phosphorylation it is often referred to as Aerobic Glycolysis (AG). AG is a biomarker of a group of metabolic functions broadly supporting biosynthesis and neuroprotection. The distribution of AG in normal young adults correlates spatially with Aβ deposition in AD patients and cognitively normal individuals with elevated Aβ. In transgenic mice extracellular fluid Aβ and lactate, a marker of AG, vary in parallel regionally and with changes in activity. Reducing neuronal activity locally in transgenic mice attenuates plaque formation suggesting that plaque formation is an activity dependent process associated with Aerobic Glycolysis.
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regional Aerobic Glycolysis in the human brain
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Neil S Vaishnavi, Andrei G Vlassenko, Melissa M Rundle, Abraham Z Snyder, Mark A Mintun, Marcus E RaichleAbstract:Aerobic Glycolysis is defined as glucose utilization in excess of that used for oxidative phosphorylation despite sufficient oxygen to completely metabolize glucose to carbon dioxide and water. Aerobic Glycolysis is present in the normal human brain at rest and increases locally during increased neuronal activity; yet its many biological functions have received scant attention because of a prevailing energy-centric focus on the role of glucose as substrate for oxidative phosphorylation. As an initial step in redressing this neglect, we measured the regional distribution of Aerobic Glycolysis with positron emission tomography in 33 neurologically normal young adults at rest. We show that the distribution of Aerobic Glycolysis in the brain is differentially present in previously well-described functional areas. In particular, Aerobic Glycolysis is significantly elevated in medial and lateral parietal and prefrontal cortices. In contrast, the cerebellum and medial temporal lobes have levels of Aerobic Glycolysis significantly below the brain mean. The levels of Aerobic Glycolysis are not strictly related to the levels of brain energy metabolism. For example, sensory cortices exhibit high metabolic rates for glucose and oxygen consumption but low rates of Aerobic Glycolysis. These striking regional variations in Aerobic Glycolysis in the normal human brain provide an opportunity to explore how brain systems differentially use the diverse cell biology of glucose in support of their functional specializations in health and disease.
Andrei G Vlassenko - One of the best experts on this subject based on the ideXlab platform.
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Aerobic Glycolysis and tau deposition in preclinical alzheimer s disease
Neurobiology of Aging, 2018Co-Authors: Andrei G Vlassenko, Manu S Goyal, Tyler Blazey, Lars E Couture, Tony J Durbin, John C Morris, Brian A Gordon, Jon Christensen, Hussain Jafri, Marcus E RaichleAbstract:Abstract Research of the human brain metabolism in vivo has largely focused on total glucose use (via fluorodeoxyglucose positron emission tomography) and, until recently, did not examine the use of glucose outside oxidative phosphorylation, which is known as Aerobic Glycolysis (AG). AG supports important functions including biosynthesis and neuroprotection but decreases dramatically with aging. This multitracer positron emission tomography study evaluated the relationship between AG, total glucose use (CMRGlc), oxygen metabolism (CMRO2), tau, and amyloid deposition in 42 individuals, including those at preclinical and symptomatic stages of Alzheimer's disease. Our findings demonstrate that in individuals with amyloid burden, lower AG is associated with higher tau deposition. No such correlation was observed for CMRGlc or CMRO2. We suggest that aging-related loss of AG leading to decreased synaptic plasticity and neuroprotection may accelerate tauopathy in individuals with amyloid burden. Longitudinal AG and Alzheimer's disease pathology studies are needed to verify causality.
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loss of brain Aerobic Glycolysis in normal human aging
Cell Metabolism, 2017Co-Authors: Manu S Goyal, Andrei G Vlassenko, Tyler Blazey, Yi Su, Lars E Couture, Tony J Durbin, Randall J Bateman, Tammie L S Benzinger, John C Morris, Marcus E RaichleAbstract:Summary The normal aging human brain experiences global decreases in metabolism, but whether this affects the topography of brain metabolism is unknown. Here we describe PET-based measurements of brain glucose uptake, oxygen utilization, and blood flow in cognitively normal adults from 20 to 82 years of age. Age-related decreases in brain glucose uptake exceed that of oxygen use, resulting in loss of brain Aerobic Glycolysis (AG). Whereas the topographies of total brain glucose uptake, oxygen utilization, and blood flow remain largely stable with age, brain AG topography changes significantly. Brain regions with high AG in young adults show the greatest change, as do regions with prolonged developmental transcriptional features (i.e., neoteny). The normal aging human brain thus undergoes characteristic metabolic changes, largely driven by global loss and topographic changes in brain AG.
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brain Aerobic Glycolysis and motor adaptation learning
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Benjamin J Shannon, Andrei G Vlassenko, Sanjeev N Vaishnavi, Joshua S Shimony, Jerrel Rutlin, Marcus E RaichleAbstract:Ten percent to 15% of glucose used by the brain is metabolized nonoxidatively despite adequate tissue oxygenation, a process termed Aerobic Glycolysis (AG). Because of the known role of Glycolysis in biosynthesis, we tested whether learning-induced synaptic plasticity would lead to regionally appropriate, learning-dependent changes in AG. Functional MRI (fMRI) before, during, and after performance of a visual–motor adaptation task demonstrated that left Brodmann area 44 (BA44) played a key role in adaptation, with learning-related changes to activity during the task and altered resting-state, functional connectivity after the task. PET scans before and after task performance indicated a sustained increase in AG in left BA 44 accompanied by decreased oxygen consumption. Intersubject variability in behavioral adaptation rate correlated strongly with changes in AG in this region, as well as functional connectivity, which is consistent with a role for AG in synaptic plasticity.
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brain Aerobic Glycolysis functions and alzheimer s disease
Clinical and Translational Imaging, 2015Co-Authors: Andrei G Vlassenko, Marcus E RaichleAbstract:Genetic, biochemical, pathological, and biomarker data demonstrate that Alzheimer's disease (AD) pathology, including the initiation and progressive buildup of insoluble forms of beta-amyloid (Aβ), appears to begin ~ 10-15 years prior to the onset of cognitive decline associated with AD. Metabolic dysfunction, a prominent feature of the evolving brain pathology, is reflected in a decline of total glucose utilization. Despite decades of interest in declining glucose use in AD no detailed consideration had been given to the possibility that this decline is not just a decline in energy consumption but rather in Glycolysis alone. Glycolysis is a multi-step process that prepares the glucose molecule for oxidative phosphorylation and the generation of energy. In the normal brain, Glycolysis exceeds that required for the needs of oxidative phosphorylation. Because it is occurring in a setting with adequate oxygen available for oxidative phosphorylation it is often referred to as Aerobic Glycolysis (AG). AG is a biomarker of a group of metabolic functions broadly supporting biosynthesis and neuroprotection. The distribution of AG in normal young adults correlates spatially with Aβ deposition in AD patients and cognitively normal individuals with elevated Aβ. In transgenic mice extracellular fluid Aβ and lactate, a marker of AG, vary in parallel regionally and with changes in activity. Reducing neuronal activity locally in transgenic mice attenuates plaque formation suggesting that plaque formation is an activity dependent process associated with Aerobic Glycolysis.
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regional Aerobic Glycolysis in the human brain
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Neil S Vaishnavi, Andrei G Vlassenko, Melissa M Rundle, Abraham Z Snyder, Mark A Mintun, Marcus E RaichleAbstract:Aerobic Glycolysis is defined as glucose utilization in excess of that used for oxidative phosphorylation despite sufficient oxygen to completely metabolize glucose to carbon dioxide and water. Aerobic Glycolysis is present in the normal human brain at rest and increases locally during increased neuronal activity; yet its many biological functions have received scant attention because of a prevailing energy-centric focus on the role of glucose as substrate for oxidative phosphorylation. As an initial step in redressing this neglect, we measured the regional distribution of Aerobic Glycolysis with positron emission tomography in 33 neurologically normal young adults at rest. We show that the distribution of Aerobic Glycolysis in the brain is differentially present in previously well-described functional areas. In particular, Aerobic Glycolysis is significantly elevated in medial and lateral parietal and prefrontal cortices. In contrast, the cerebellum and medial temporal lobes have levels of Aerobic Glycolysis significantly below the brain mean. The levels of Aerobic Glycolysis are not strictly related to the levels of brain energy metabolism. For example, sensory cortices exhibit high metabolic rates for glucose and oxygen consumption but low rates of Aerobic Glycolysis. These striking regional variations in Aerobic Glycolysis in the normal human brain provide an opportunity to explore how brain systems differentially use the diverse cell biology of glucose in support of their functional specializations in health and disease.
Chuanyong Guo - One of the best experts on this subject based on the ideXlab platform.
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emerging roles and the regulation of Aerobic Glycolysis in hepatocellular carcinoma
Journal of Experimental & Clinical Cancer Research, 2020Co-Authors: Jiao Feng, Weiqi Dai, Chuanyong GuoAbstract:Liver cancer has become the sixth most diagnosed cancer and the fourth leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is responsible for up to 75–85% of primary liver cancers, and sorafenib is the first targeted drug for advanced HCC treatment. However, sorafenib resistance is common because of the resultant enhancement of Aerobic Glycolysis and other molecular mechanisms. Aerobic Glycolysis was firstly found in HCC, acts as a hallmark of liver cancer and is responsible for the regulation of proliferation, immune evasion, invasion, metastasis, angiogenesis, and drug resistance in HCC. The three rate-limiting enzymes in the glycolytic pathway, including hexokinase 2 (HK2), phosphofructokinase 1 (PFK1), and pyruvate kinases type M2 (PKM2) play an important role in the regulation of Aerobic Glycolysis in HCC and can be regulated by many mechanisms, such as the AMPK, PI3K/Akt pathway, HIF-1α, c-Myc and noncoding RNAs. Because of the importance of Aerobic Glycolysis in the progression of HCC, targeting key factors in its pathway such as the inhibition of HK2, PFK or PKM2, represent potential new therapeutic approaches for the treatment of HCC.
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genistein suppresses Aerobic Glycolysis and induces hepatocellular carcinoma cell death
British Journal of Cancer, 2017Co-Authors: Weiqi Dai, Jiao Feng, Qinghui Zhang, Tong Liu, Wenwen Wang, Kan Chen, Yujing Xia, Yingqun Zhou, Xiaoming Fan, Chuanyong GuoAbstract:Genistein is a natural isoflavone with many health benefits, including antitumour effects. Increased hypoxia-inducible factor 1 α (HIF-1α) levels and Glycolysis in tumour cells are associated with an increased risk of mortality, cancer progression, and resistance to therapy. However, the effect of genistein on HIF-1α and Glycolysis in hepatocellular carcinoma (HCC) is still unclear. Cell viability, apoptosis rate, lactate production, and glucose uptake were measured in HCC cell lines with genistein incubation. Lentivirus-expressed glucose transporter 1 (GLUT1) or/and hexokinase 2 (HK2) and siRNA of HIF-1α were used to test the direct target of genistein. Subcutaneous xenograft mouse models were used to measure in vivo efficacy of genistein and its combination with sorafenib. Genistein inhibited Aerobic Glycolysis and induced mitochondrial apoptosis in HCC cells. Neither inhibitors nor overexpression of HK2 or GLUTs enhance or alleviate this effect. Although stabiliser of HIF-1α reversed the effect of genistein, genistein no longer has effects on HIF-1α siRNA knockdown HCC cells. In addition, genistein enhanced the antitumour effect of sorafenib in sorafenib-resistant HCC cells and HCC-bearing mice. Genistein sensitised Aerobic glycolytic HCC cells to apoptosis by directly downregulating HIF-1α, therefore inactivating GLUT1 and HK2 to suppress Aerobic Glycolysis. The inhibitory effect of genistein on tumour cell growth and Glycolysis may help identify effective treatments for HCC patients at advanced stages.
Huaqin Wang - One of the best experts on this subject based on the ideXlab platform.
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bag3 directly stabilizes hexokinase 2 mrna and promotes Aerobic Glycolysis in pancreatic cancer cells
Journal of Cell Biology, 2017Co-Authors: Huaqin Wang, Mingxin An, Jiamei Wang, Xiaona Meng, Si Li, Chao Li, Xinyu LiAbstract:Aerobic Glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in Aerobic Glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in Glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the Aerobic Glycolysis pathway for developing novel anticancer agents.
Weiqi Dai - One of the best experts on this subject based on the ideXlab platform.
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emerging roles and the regulation of Aerobic Glycolysis in hepatocellular carcinoma
Journal of Experimental & Clinical Cancer Research, 2020Co-Authors: Jiao Feng, Weiqi Dai, Chuanyong GuoAbstract:Liver cancer has become the sixth most diagnosed cancer and the fourth leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is responsible for up to 75–85% of primary liver cancers, and sorafenib is the first targeted drug for advanced HCC treatment. However, sorafenib resistance is common because of the resultant enhancement of Aerobic Glycolysis and other molecular mechanisms. Aerobic Glycolysis was firstly found in HCC, acts as a hallmark of liver cancer and is responsible for the regulation of proliferation, immune evasion, invasion, metastasis, angiogenesis, and drug resistance in HCC. The three rate-limiting enzymes in the glycolytic pathway, including hexokinase 2 (HK2), phosphofructokinase 1 (PFK1), and pyruvate kinases type M2 (PKM2) play an important role in the regulation of Aerobic Glycolysis in HCC and can be regulated by many mechanisms, such as the AMPK, PI3K/Akt pathway, HIF-1α, c-Myc and noncoding RNAs. Because of the importance of Aerobic Glycolysis in the progression of HCC, targeting key factors in its pathway such as the inhibition of HK2, PFK or PKM2, represent potential new therapeutic approaches for the treatment of HCC.
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genistein suppresses Aerobic Glycolysis and induces hepatocellular carcinoma cell death
British Journal of Cancer, 2017Co-Authors: Weiqi Dai, Jiao Feng, Qinghui Zhang, Tong Liu, Wenwen Wang, Kan Chen, Yujing Xia, Yingqun Zhou, Xiaoming Fan, Chuanyong GuoAbstract:Genistein is a natural isoflavone with many health benefits, including antitumour effects. Increased hypoxia-inducible factor 1 α (HIF-1α) levels and Glycolysis in tumour cells are associated with an increased risk of mortality, cancer progression, and resistance to therapy. However, the effect of genistein on HIF-1α and Glycolysis in hepatocellular carcinoma (HCC) is still unclear. Cell viability, apoptosis rate, lactate production, and glucose uptake were measured in HCC cell lines with genistein incubation. Lentivirus-expressed glucose transporter 1 (GLUT1) or/and hexokinase 2 (HK2) and siRNA of HIF-1α were used to test the direct target of genistein. Subcutaneous xenograft mouse models were used to measure in vivo efficacy of genistein and its combination with sorafenib. Genistein inhibited Aerobic Glycolysis and induced mitochondrial apoptosis in HCC cells. Neither inhibitors nor overexpression of HK2 or GLUTs enhance or alleviate this effect. Although stabiliser of HIF-1α reversed the effect of genistein, genistein no longer has effects on HIF-1α siRNA knockdown HCC cells. In addition, genistein enhanced the antitumour effect of sorafenib in sorafenib-resistant HCC cells and HCC-bearing mice. Genistein sensitised Aerobic glycolytic HCC cells to apoptosis by directly downregulating HIF-1α, therefore inactivating GLUT1 and HK2 to suppress Aerobic Glycolysis. The inhibitory effect of genistein on tumour cell growth and Glycolysis may help identify effective treatments for HCC patients at advanced stages.
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by reducing hexokinase 2 resveratrol induces apoptosis in hcc cells addicted to Aerobic Glycolysis and inhibits tumor growth in mice
Oncotarget, 2015Co-Authors: Weiqi Dai, Tong Liu, Kan Chen, Yujing Xia, Fan Wang, Yuanyuan Zheng, Jianrong Wang, Yuqing ZhouAbstract:Cancer cells exhibit an altered metabolic phenotype known as the Aerobic Glycolysis. The expression of HK2 changes the metabolic phenotype of cells to support cancerous growth. In the present study, we investigated the inhibitory effect of resveratrol on HK2 expression and hepatocellular carcinoma (HCC) cell Glycolysis. Aerobic Glycolysis was observed in four HCC cell lines compared to the normal hepatic cells. Resveratrol sensitized Aerobic glycolytic HCC cells to apoptosis, and this effect was attenuated by glycolytic inhibitors. The induction of mitochondrial apoptosis was associated with the decrease of HK2 expression by resveratrol in HCC cells. In addition, resveratrol enhanced sorafenib induced cell growth inhibition in Aerobic glycolytic HCC cells. Combination treatment with both reagents inhibited the growth and promoted apoptosis of HCC-bearing mice. The reduction of HK2 by resveratrol provides a new dimension to clinical HCC therapies aimed at preventing disease progression.