bims-glecem Biomed News
on Glycogen metabolism in exercise, cancer and energy metabolism
Issue of 2023‒07‒09
six papers selected by
Dipsikha Biswas, Københavns Universitet
  1. Glycogen accumulation modulates life span in a mouse model of amyotrophic lateral sclerosis.
  2. Computational insights into novel inhibitor indole-heterocycle specific against glycogen phosphorylase isoenzymes interaction mechanism.
  3. MK8617 inhibits M1 macrophage polarization and inflammation via the HIF-1α/GYS1/UDPG/P2Y14 pathway.
  4. Protective effect of manganese treatment on insulin resistance in HepG2 hepatocytes.
  5. A flavonoid-rich fraction of Euphorbia peplus attenuates hyperglycemia, insulin resistance, and oxidative stress in a type 2 diabetes rat model.
  6. Metabolomics analysis reveals changes related to pseudocyst formation induced by iron depletion in Trichomonas vaginalis.
  1. J Neurochem. 2023 Jul 04.
    Glycogen accumulation modulates life span in a mouse model of amyotrophic lateral sclerosis.
    M Kathryn Brewer, Pascual Torres, Victòria Ayala, Manuel Portero-Otin, Reinald Pamplona, Pol Andrés-Benito, Isidro Ferrer, Joan J Guinovart, Jordi Duran.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord. Glial cells, including astrocytes and microglia, have been shown to contribute to neurodegeneration in ALS, and metabolic dysfunction plays an important role in the progression of the disease. Glycogen is a soluble polymer of glucose found at low levels in the central nervous system that plays an important role in memory formation, synaptic plasticity, and the prevention of seizures. However, its accumulation in astrocytes and/or neurons is associated with pathological conditions and aging. Importantly, glycogen accumulation has been reported in the spinal cord of human ALS patients and mouse models. In the present work, using the SOD1G93A mouse model of ALS, we show that glycogen accumulates in the spinal cord and brainstem during symptomatic and end stages of the disease and that the accumulated glycogen is associated with reactive astrocytes. To study the contribution of glycogen to ALS progression, we generated SOD1G93A mice with reduced glycogen synthesis (SOD1G93A GShet mice). SOD1G93A GShet mice had a significantly longer life span than SOD1G93A mice and showed lower levels of the astrocytic pro-inflammatory cytokine Cxcl10, suggesting that the accumulation of glycogen is associated with an inflammatory response. Supporting this, inducing an increase in glycogen synthesis reduced life span in SOD1G93A mice. Altogether, these results suggest that glycogen in reactive astrocytes contributes to neurotoxicity and disease progression in ALS.
    Keywords:  amyotrophic lateral sclerosis; astrocytes; glycogen; motor neurons; neurodegeneration; spinal cord
    DOI:  https://doi.org/10.1111/jnc.15906
  2. Future Med Chem. 2023 Jul 03.
    Computational insights into novel inhibitor indole-heterocycle specific against glycogen phosphorylase isoenzymes interaction mechanism.
    Youde Wang, Shuai Li, Zhiwei Yan, Yachun Guo, Liying Zhang.
      Background: Glycogen phosphorylase (GP) is a potential drug target. As the three subtypes of GP are highly conserved, it is difficult to research their specificity. However, compound 1 inhibits the GP subtypes differently and was studied to aid in designing specific inhibitors. Results: Molecular docking showed that the ligands in GP subtype complexes had some differences in spatial conformation and binding modes, stabilized by polar and nonpolar interactions. The results were confirmed through kinetic experiments, with affinities of -85.230 (brain GP), -73.809 (liver GP) and -66.061 kJ/mol (muscle GP). Conclusion: The study provides insight into the possible reasons for differences in compound 1's inhibitory activity against the GP subtypes and offers guidance in designing target molecules for regulating selectivity among the subtypes.
    Keywords:  GP subtypes; glycogen phosphorylase; heterocyclic derivative; molecular docking; molecular dynamics
    DOI:  https://doi.org/10.4155/fmc-2023-0084
  3. PeerJ. 2023 ;11 e15591
    MK8617 inhibits M1 macrophage polarization and inflammation via the HIF-1α/GYS1/UDPG/P2Y14 pathway.
    Lingling Qian, Xiao-Qin Chen, Deyang Kong, Gaoyuan Wang, Yun Cao, Yingchun Xiao, Jing-Yuan Cao, Chunbo Zou.
      Background: Nonresolving inflammation is a major driver of disease and needs to be taken seriously. Hypoxia-inducible factor (HIF) is closely associated with inflammation. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs), as stabilizers of HIF, have recently been reported to have the ability to block inflammation. We used MK8617, a novel HIF-PHI, to study its effect on macrophage inflammation and to explore its possible mechanisms.Methods: Cell viability after MK8617 and lipopolysaccharide (LPS) addition was assessed by Cell Counting Kit-8 (CCK8) to find the appropriate drug concentration. MK8617 pretreated or unpretreated cells were then stimulated with LPS to induce macrophage polarization and inflammation. Inflammatory indicators in cells were assessed by real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR), western blot (WB) and immunofluorescence (IF). The level of uridine diphosphate glucose (UDPG) in the cell supernatant was measured by ELISA. Purinergic G protein-coupled receptor P2Y14, as well as hypoxia-inducible factor-1α (HIF-1α) and glycogen synthase 1 (GYS1) were detected by qRT-PCR and WB. After UDPG inhibition with glycogen phosphorylase inhibitor (GPI) or knockdown of HIF-1α and GYS1 with lentivirus, P2Y14 and inflammatory indexes of macrophages were detected by qRT-PCR and WB.
    Results: MK8617 reduced LPS-induced release of pro-inflammatory factors as well as UDPG secretion and P2Y14 expression. UDPG upregulated P2Y14 and inflammatory indicators, while inhibition of UDPG suppressed LPS-induced inflammation. In addition, HIF-1α directly regulated GYS1, which encoded glycogen synthase, an enzyme that mediated the synthesis of glycogen by UDPG, thereby affecting UDPG secretion. Knockdown of HIF-1α and GYS1 disrupted the anti-inflammatory effect of MK8617.
    Conclusions: Our study demonstrated the role of MK8617 in macrophage inflammation and revealed that its mechanism of action may be related to the HIF-1α/GYS1/UDPG/P2Y14 pathway, providing new therapeutic ideas for the study of inflammation.
    Keywords:  Glycogen synthase 1; Hypoxia-inducible factor-prolylhydroxylase inhibitor; Inflammation; Uridine diphosphate glucose/P2Y14 signaling pathway
    DOI:  https://doi.org/10.7717/peerj.15591
  4. Nutr Hosp. 2023 Jun 26.
    Protective effect of manganese treatment on insulin resistance in HepG2 hepatocytes.
    Qingwen Zhang, Shili Song, Ruyue Jiang, Jingyi Zhang, Lixin Na.
      OBJECTIVES: manganese (Mn) is closely related to type 2 diabetes mellitus and insulin resistance (IR), but the exact mechanism is unclear. This study aimed to explore the regulatory effects and mechanism of Mn on IR using hepatocyte IR model induced by high palmitate (PA), high glucose (HG) or insulin.METHODS: HepG2 cells were exposed to PA (200 μM), HG (25 mM) or insulin (100 nM) respectively, alone or with 5 μM Mn for 24 hours. The expression of key proteins in insulin signaling pathway, intracellular glycogen content and glucose accumulation, reactive oxygen species (ROS) level and Mn superoxide dismutase (MnSOD) activity were detected.
    RESULTS: compared with control group, the expression of phosphorylated protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β) and forkhead box O1 (FOXO1) in the three IR groups was declined, and this decrease was reversed by Mn. The reduction of intracellular glycogen content and increase in glucose accumulation in IR groups were also inhibited by Mn. Additionally, the production of ROS was increased in IR models, compared with normal control group, while Mn reduced the excessive production of ROS induced by PA, HG or insulin. However, Mn did not alter the activity of MnSOD in the three IR models.
    CONCLUSION: this study demonstrated that Mn treatment can improve IR in hepatocytes. The mechanism is probably by reducing the level of intracellular oxidative stress, enhancing the activity of Akt/GSK-3β/FOXO1 signal pathway, promoting glycogen synthesis, and inhibiting gluconeogenesis.
    DOI:  https://doi.org/10.20960/nh.04521
  5. Front Pharmacol. 2023 ;14 1204641
    A flavonoid-rich fraction of Euphorbia peplus attenuates hyperglycemia, insulin resistance, and oxidative stress in a type 2 diabetes rat model.
    Reem S Alruhaimi, Gomaa Mostafa-Hedeab, Maisa Siddiq Abduh, Albandari Bin-Ammar, Emad H M Hassanein, Emadeldin M Kamel, Ayman M Mahmoud.
      Background: Type 2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance (IR) and hyperglycemia. Plants are valuable sources of therapeutic agents for the management of T2D. Euphorbia peplus has been widely used as a traditional medicine for the treatment of various diseases, but its beneficial role in T2D has not been fully explored. Methods: The anti-diabetic efficacy of E. peplus extract (EPE) was studied using rats with T2D induced by high-fat diet (HFD) and streptozotocin (STZ). The diabetic rats received 100, 200, and 400 mg/kg EPE for 4 weeks. Results: Phytochemical fractionation of the aerial parts of E. peplus led to the isolation of seven known flavonoids. Rats with T2D exhibited IR, impaired glucose tolerance, decreased liver hexokinase and glycogen, and upregulated glycogen phosphorylase, glucose-6-phosphatase (G-6-Pase), and fructose-1,6-bisphosphatase (F-1,6-BPase). Treatment with 100, 200, and 400 mg/kg EPE for 4 weeks ameliorated hyperglycemia, IR, liver glycogen, and the activities of carbohydrate-metabolizing enzymes. EPE attenuated dyslipidemia, serum transaminases, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and liver lipid accumulation, nuclear factor (NF)-κB p65, and lipid peroxidation, nitric oxide and enhanced antioxidants. All EPE doses upregulated serum adiponectin and liver peroxisome proliferator-activated receptor γ (PPARγ) in HFD/STZ-induced rats. The isolated flavonoids showed in silico binding affinity toward hexokinase, NF-κB, and PPARγ. Conclusion: E. peplus is rich in flavonoids, and its extract ameliorated IR, hyperglycemia, dyslipidemia, inflammation and redox imbalance, and upregulated adiponectin and PPARγ in rats with T2D.
    Keywords:  Euphorbia; diabetes; inflammation; insulin resistance; oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2023.1204641
  6. Parasit Vectors. 2023 Jul 06. 16(1): 226
    Metabolomics analysis reveals changes related to pseudocyst formation induced by iron depletion in Trichomonas vaginalis.
    Wei-Hung Cheng, Po-Jung Huang, Chi-Ching Lee, Yuan-Ming Yeh, Seow-Chin Ong, Rose Lin, Fu-Man Ku, Cheng-Hsun Chiu, Petrus Tang.
      BACKGROUND: Iron is an essential element for cellular functions, such as energy metabolism. Trichomonas vaginalis, a human urogenital tract pathogen, is capable of surviving in the environment without sufficient iron supplementation. Pseudocysts (cyst-like structures) are an environmentally tolerated stage of this parasite while encountering undesired conditions, including iron deficiency. We previously demonstrated that iron deficiency induces more active glycolysis but a drastic downregulation of hydrogenosomal energy metabolic enzymes. Therefore, the metabolic direction of the end product of glycolysis is still controversial.METHODS: In the present work, we conducted an LC‒MS-based metabolomics analysis to obtain accurate insights into the enzymatic events of T. vaginalis under iron-depleted (ID) conditions.
    RESULTS: First, we showed the possible digestion of glycogen, cellulose polymerization, and accumulation of raffinose family oligosaccharides (RFOs). Second, a medium-chain fatty acid (MCFA), capric acid, was elevated, whereas most detected C18 fatty acids were reduced significantly. Third, amino acids were mostly reduced, especially alanine, glutamate, and serine. Thirty-three dipeptides showed significant accumulation in ID cells, which was probably associated with the decrease in amino acids. Our results indicated that glycogen was metabolized as the carbon source, and the structural component cellulose was synthesized at same time. The decrease in C18 fatty acids implied possible incorporation in the membranous compartment for pseudocyst formation. The decrease in amino acids accompanied by an increase in dipeptides implied incomplete proteolysis. These enzymatic reactions (alanine dehydrogenase, glutamate dehydrogenase, and threonine dehydratase) were likely involved in ammonia release.
    CONCLUSION: These findings highlighted the possible glycogen utilization, cellulose biosynthesis, and fatty acid incorporation in pseudocyst formation as well as NO precursor ammonia production induced by iron-depleted stress.
    Keywords:  Amino acids; Ammonia; Cellulose; Dipeptides; Fatty acids; Glycogen; Iron deficiency; Metabolomics analysis; Trichomonas vaginalis
    DOI:  https://doi.org/10.1186/s13071-023-05842-w
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