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Brain Research Bulletin Jul 2023Impairments in systematic and regional glucose metabolism exist in patients with Parkinson's disease (PD) at every stage of the disease course, and such impairments are... (Review)
Review
Impairments in systematic and regional glucose metabolism exist in patients with Parkinson's disease (PD) at every stage of the disease course, and such impairments are associated with the incidence, progression, and special phenotypes of PD, which affect each physiological process of glucose metabolism including glucose uptake, glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and pentose phosphate shunt pathway. These impairments may be attributed to various mechanisms, such as insulin resistance, oxidative stress, abnormal glycated modification, blood-brain-barrier dysfunction, and hyperglycemia-induced damages. These mechanisms could subsequently cause excessive methylglyoxal and reactive oxygen species production, neuroinflammation, abnormal aggregation of protein, mitochondrial dysfunction, and decreased dopamine, and finally result in energy supply insufficiency, neurotransmitter dysregulation, aggregation and phosphorylation of α-synuclein, and dopaminergic neuron loss. This review discusses the glucose metabolism impairment in PD and its pathophysiological mechanisms, and briefly summarized the currently-available therapies targeting glucose metabolism impairment in PD, including glucagon-likepeptide-1 (GLP-1) receptor agonists and dual GLP-1/gastric inhibitory peptide receptor agonists, metformin, and thiazoledinediones.
Topics: Humans; Parkinson Disease; Hyperglycemia; Glycolysis; Dopamine; Glucose; Glucagon-Like Peptide 1; Dopaminergic Neurons
PubMed: 37210012
DOI: 10.1016/j.brainresbull.2023.110672 -
Biomedicine & Pharmacotherapy =... Jul 2023Myocardial ischemia-reperfusion injury is a common condition in cardiovascular diseases, and the mechanism of its occurrence involves multiple complex metabolic pathways... (Review)
Review
Myocardial ischemia-reperfusion injury is a common condition in cardiovascular diseases, and the mechanism of its occurrence involves multiple complex metabolic pathways and signaling pathways. Among these pathways, glucose metabolism and lipid metabolism play important roles in regulating myocardial energy metabolism. Therefore, this article focuses on the roles of glucose metabolism and lipid metabolism in myocardial ischemia-reperfusion injury, including glycolysis, glucose uptake and transport, glycogen metabolism and the pentose phosphate pathway; and triglyceride metabolism, fatty acid uptake and transport, phospholipid metabolism, lipoprotein metabolism, and cholesterol metabolism. Finally, due to the different alterations and development of glucose metabolism and lipid metabolism in myocardial ischemia-reperfusion, there are also complex interregulatory relationships between them. In the future, modulating the equilibrium between glucose metabolism and lipid metabolism in cardiomyocytes and ameliorating aberrations in myocardial energy metabolism represent highly promising novel strategies for addressing myocardial ischemia-reperfusion injury. Therefore, a comprehensive exploration of glycolipid metabolism can offer novel theoretical and clinical insights into the prevention and treatment of myocardial ischemia-reperfusion injury.
Topics: Humans; Myocardial Reperfusion Injury; Glucose; Lipid Metabolism; Myocardial Ischemia; Myocardium
PubMed: 37141734
DOI: 10.1016/j.biopha.2023.114827 -
Nature Communications Sep 2023MAVS is an adapter protein involved in RIG-I-like receptor (RLR) signaling in mitochondria, peroxisomes, and mitochondria-associated ER membranes (MAMs). However, the...
MAVS is an adapter protein involved in RIG-I-like receptor (RLR) signaling in mitochondria, peroxisomes, and mitochondria-associated ER membranes (MAMs). However, the role of MAVS in glucose metabolism and RLR signaling cross-regulation and how these signaling pathways are coordinated among these organelles have not been defined. This study reports that RLR action drives a switch from glycolysis to the pentose phosphate pathway (PPP) and the hexosamine biosynthesis pathway (HBP) through MAVS. We show that peroxisomal MAVS is responsible for glucose flux shift into PPP and type III interferon (IFN) expression, whereas MAMs-located MAVS is responsible for glucose flux shift into HBP and type I IFN expression. Mechanistically, peroxisomal MAVS interacts with G6PD and the MAVS signalosome forms at peroxisomes by recruiting TNF receptor-associated factor 6 (TRAF6) and interferon regulatory factor 1 (IRF1). By contrast, MAMs-located MAVS interact with glutamine-fructose-6-phosphate transaminase, and the MAVS signalosome forms at MAMs by recruiting TRAF6 and TRAF2. Our findings suggest that MAVS mediates the interaction of RLR signaling and glucose metabolism.
Topics: Adaptor Proteins, Signal Transducing; Glucose; Glycolysis; Hexosamines; Pentose Phosphate Pathway; TNF Receptor-Associated Factor 6; Humans; Animals; Mice; Signal Transduction
PubMed: 37660168
DOI: 10.1038/s41467-023-41028-9 -
Frontiers in Endocrinology 2023Diabetic nephropathy (DN), which is the main cause of renal failure in end-stage renal disease, is becoming a common chronic renal disease worldwide. Mendelian...
BACKGROUND
Diabetic nephropathy (DN), which is the main cause of renal failure in end-stage renal disease, is becoming a common chronic renal disease worldwide. Mendelian randomization (MR) is a genetic tool that is widely used to minimize confounding and reverse causation when identifying the causal effects of complex traits. In this study, we conducted an integrated multiple microarray analysis and large-scale plasma proteome MR analysis to identify candidate biomarkers and evaluate the causal effects of prospective therapeutic targets in DN.
METHODS
Five DN gene expression datasets were selected from the Gene Expression Omnibus. The robust rank aggregation (RRA) method was used to integrate differentially expressed genes (DEGs) of glomerular samples between patients with DN and controls, followed by functional enrichment analysis. Protein quantitative trait loci were incorporated from seven different proteomic genome-wide association studies, and genetic association data on DN were obtained from FinnGen (3676 cases and 283,456 controls) for two-sample MR analysis. External validation and clinical correlation were also conducted.
RESULTS
A total of 82 DEGs (53 upregulated and 29 downregulated) were identified through RRA integrated analysis. The enriched Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes pathways of the DEGs were significantly enriched in neutrophil degranulation, neutrophil activation, proteoglycan binding, collagen binding, secretory granule lumen, gluconeogenesis, tricarboxylic acid cycle, and pentose phosphate pathways. MR analysis revealed that the genetically predicted levels of MHC class I polypeptide-related sequence B (MICB), granzyme A (GZMA), cathepsin S (CTSS), chloride intracellular channel protein 5, and ficolin-1 (FCN1) were causally associated with DN risk. Expression validation and clinical correlation analysis showed that MICB, GZMA, FCN1, and insulin-like growth factor 1 may participate in the development of DN, and carbonic anhydrase 2 and lipoprotein lipase may play protective roles in patients with DN.
CONCLUSION
Our integrated analysis identified novel biomarkers, including MICB and GZMA, which may help further understand the complicated mechanisms of DN and identify new target pathways for intervention.
Topics: Humans; Diabetic Nephropathies; Gene Expression Profiling; Genome-Wide Association Study; Proteomics; Mendelian Randomization Analysis; Microarray Analysis; Biomarkers; Quantitative Trait Loci; Diabetes Mellitus
PubMed: 37492198
DOI: 10.3389/fendo.2023.1191768 -
The Journal of Clinical Investigation Dec 2023Elevation of reactive oxygen species (ROS) levels is a general consequence of tumor cells' response to treatment and may cause tumor cell death. Mechanisms by which...
Elevation of reactive oxygen species (ROS) levels is a general consequence of tumor cells' response to treatment and may cause tumor cell death. Mechanisms by which tumor cells clear fatal ROS, thereby rescuing redox balance and entering a chemoresistant state, remain unclear. Here, we show that cysteine sulfenylation by ROS confers on aryl hydrocarbon receptor (AHR) the ability to dissociate from the heat shock protein 90 complex but to bind to the PPP1R3 family member PPP1R3C of the glycogen complex in drug-treated tumor cells, thus activating glycogen phosphorylase to initiate glycogenolysis and the subsequent pentose phosphate pathway, leading to NADPH production for ROS clearance and chemoresistance formation. We found that basic ROS levels were higher in chemoresistant cells than in chemosensitive cells, guaranteeing the rapid induction of AHR sulfenylation for the clearance of excess ROS. These findings reveal that AHR can act as an ROS sensor to mediate chemoresistance, thus providing a potential strategy to reverse chemoresistance in patients with cancer.
Topics: Humans; Reactive Oxygen Species; Drug Resistance, Neoplasm; Receptors, Aryl Hydrocarbon; Glycogenolysis; Neoplasms
PubMed: 38099490
DOI: 10.1172/JCI170753 -
The Journal of Clinical Investigation Dec 2023Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved...
Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved steroid-sparing alternatives. Here, we investigated the mechanism of granuloma formation using single-cell RNA-Seq in sarcoidosis patients. We observed that the percentages of triggering receptor expressed on myeloid cells 2-positive (TREM2-positive) macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, diagnostic makers of sarcoidosis, were increased in cutaneous sarcoidosis granulomas. Macrophages in the sarcoidosis lesion were hypermetabolic, especially in the pentose phosphate pathway (PPP). Expression of the PPP enzymes, such as fructose-1,6-bisphosphatase 1 (FBP1), was elevated in both systemic granuloma lesions and serum of sarcoidosis patients. Granuloma formation was attenuated by the PPP inhibitors in in vitro giant cell and in vivo murine granuloma models. These results suggest that the PPP may be a promising target for developing therapeutics for sarcoidosis.
Topics: Humans; Animals; Mice; Pentose Phosphate Pathway; Sarcoidosis; Granuloma; Macrophages; Glucocorticoids
PubMed: 38038136
DOI: 10.1172/JCI171088 -
International Journal of Biological... 2024Disulfidptosis occurs as a result of the accumulation of intracellular cystine followed by disulfide stress in actin cytoskeleton proteins due to a reduction of NADPH...
Disulfidptosis occurs as a result of the accumulation of intracellular cystine followed by disulfide stress in actin cytoskeleton proteins due to a reduction of NADPH produced through the pentose phosphate pathway in cells with high expression of SLC7A11. It is a cell death caused by the redox imbalance resulting from the disruption of amino acid metabolism and glucose metabolism. The discovery of disulfidptosis has sparked immense enthusiasm, but there are numerous unresolved issues that need to be addressed. Solutions to these riddles will provide insights into the detailed mechanisms and the pathophysiological relevance of disulfidptosis and utilizing disulfidptosis as an actionable therapeutic target.
Topics: Cell Death; Disulfides; Microfilament Proteins; NADP
PubMed: 38322120
DOI: 10.7150/ijbs.90606 -
Frontiers in Neuroscience 2023Astrocytes comprise half of the cells in the central nervous system and play a critical role in maintaining metabolic homeostasis. Metabolic dysfunction in astrocytes... (Review)
Review
Astrocytes comprise half of the cells in the central nervous system and play a critical role in maintaining metabolic homeostasis. Metabolic dysfunction in astrocytes has been indicated as the primary cause of neurological diseases, such as depression, Alzheimer's disease, and epilepsy. Although the metabolic functionalities of astrocytes are well known, their relationship to neurological disorders is poorly understood. The ways in which astrocytes regulate the metabolism of glucose, amino acids, and lipids have all been implicated in neurological diseases. Metabolism in astrocytes has also exhibited a significant influence on neuron functionality and the brain's neuro-network. In this review, we focused on metabolic processes present in astrocytes, most notably the glucose metabolic pathway, the fatty acid metabolic pathway, and the amino-acid metabolic pathway. For glucose metabolism, we focused on the glycolysis pathway, pentose-phosphate pathway, and oxidative phosphorylation pathway. In fatty acid metabolism, we followed fatty acid oxidation, ketone body metabolism, and sphingolipid metabolism. For amino acid metabolism, we summarized neurotransmitter metabolism and the serine and kynurenine metabolic pathways. This review will provide an overview of functional changes in astrocyte metabolism and provide an overall perspective of current treatment and therapy for neurological disorders.
PubMed: 37732313
DOI: 10.3389/fnins.2023.1217451 -
Journal of Experimental & Clinical... Jan 2024Discoidin, CUB, and LCCL domain-containing type I (DCBLD1) is identified as an oncogene involved in multiple regulation of tumor progression, but specific mechanisms...
BACKGROUND
Discoidin, CUB, and LCCL domain-containing type I (DCBLD1) is identified as an oncogene involved in multiple regulation of tumor progression, but specific mechanisms remain unclear in cervical cancer. Lactate-mediated lactylation modulates protein function. Whether DCBLD1 can be modified by lactylation and the function of DCBLD1 lactylation are unknown. Therefore, this study aims to investigate the lactylation of DCBLD1 and identify its specific lactylation sites. Herein, we elucidated the mechanism by which lactylation modification stabilizes the DCBLD1 protein. Furthermore, we investigated DCBLD1 overexpression activating pentose phosphate pathway (PPP) to promote the progression of cervical cancer.
METHODS
DCBLD1 expression was examined in human cervical cancer cells and adjacent non-tumorous tissues using quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. In vitro and in vivo studies were conducted to investigate the impact of DCBLD1 on the progression of cervical cancer. Untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics studies were used to characterize DCBLD1-induced metabolite alterations. Western blot, immunofuorescence and transmission electron microscopy were performed to detect DCBLD1 degradation of G6PD by activating autophagy. Chromatin immunoprecipitation, dual luciferase reporter assay for detecting the mechanism by which lactate increases DCBLD1 transcription. LC-MS/MS was employed to verify specific modification sites within the DCBLD1 protein.
RESULTS
We found that lactate increased DCBLD1 expression, activating the PPP to facilitate the proliferation and metastasis of cervical cancer cells. DCBLD1 primarily stimulated PPP by upregulating glucose-6-phosphate dehydrogenase (G6PD) expression and enzyme activity. The mechanism involved the increased enrichment of HIF-1α in the DCBLD1 promoter region, enhancing the DCBLD1 mRNA expression. Additionally, lactate-induced DCBLD1 lactylation stabilized DCBLD1 expression. We identified DCBLD1 as a lactylation substrate, with a predominant lactylation site at K172. DCBLD1 overexpression inhibited G6PD autophagic degradation, activating PPP to promote cervical cancer progression. In vivo, 6-An mediated inhibition of G6PD enzyme activity, inhibiting tumor proliferation.
CONCLUSIONS
Our findings revealed a novel post-translational modification type of DCBDL1, emphasizing the significance of lactylation-driven DCBDL1-mediated PPP in promoting the progression of cervical cancer.
Topics: Female; Humans; Chromatography, Liquid; Lactates; Pentose Phosphate Pathway; Tandem Mass Spectrometry; Uterine Cervical Neoplasms
PubMed: 38291438
DOI: 10.1186/s13046-024-02943-x