bims-glecem 2022-08-07 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022–08–07
eight papers selected by
Dipsikha Biswas, Københavns Universitet

Metabolic Alterations and Mitochondrial Dysfunction Underlie Hepatocellular Carcinoma Cell Death Induced by a Glycogen Metabolic Inhibitor.
Enzyme-loaded glycogen nanoparticles with tumor-targeting Activatable host-guest supramolecule for augmented chemodynamic therapy.
Editorial: Insights in exercise physiology: 2021.
Blood glucose, insulin and glycogen profiles in Sprague-Dawley rats co-infected with Plasmodium berghei ANKA and Trichinella zimbabwensis.
Glycogen metabolism reprogramming promotes inflammation in coal dust-exposed lung.
Targeting Impaired Nutrient Sensing via the Glycogen Synthase Kinase-3 Pathway With Therapeutic Compounds to Prevent or Treat Dementia: A Systematic Review.
Prolonged cycling lowers subsequent running mechanical efficiency in collegiate triathletes.
1,6-epi-Cyclophellitol Cyclosulfamidate Is a Bona Fide Lysosomal α-Glucosidase Stabilizer for the Treatment of Pompe Disease.

Biochem Pharmacol. 2022 Aug 01. pii: S0006-2952(22)00295-7. [Epub ahead of print] 115201

Metabolic Alterations and Mitochondrial Dysfunction Underlie Hepatocellular Carcinoma Cell Death Induced by a Glycogen Metabolic Inhibitor.

Shrikant Barot, Olivia Stephenson, Hari Priya Vemana, Anjali Yadav, Shraddha Bhutkar, Louis Trombetta, Vikas V Dukhande.

  Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. There is an urgent need for new targets to treat HCC due to limited treatment options and drug resistance. Many cancer cells are known to have high amount of glycogen than their tissue of origin and inhibition of glycogen catabolism induces cancer cell death by apoptosis. To further understand the role of glycogen in HCC and target it for pharmacotherapy, we studied metabolic adaptations and mitochondrial function in HepG2 cells after pharmacological inhibition of glycogen phosphorylase (GP) by CP-91149 (CP). GP inhibition increased the glycogen levels in HepG2 cells without affecting overall glucose uptake. Glycolytic capacity and importantly glycolytic reserve decreased significantly. Electron microscopy revealed that CP treatment altered mitochondrial morphology leading to mitochondrial swelling with less defined cristae. A concomitant decrease in mitochondrial oxygen consumption and mitochondria-linked ATP generation was observed. Metabolomics and enzyme activity / expression studies showed a decrease in the pentose phosphate pathway. In addition, CP treatment decreased the growth of HepG2 3D tumor spheroids in a dose- and time-dependent manner. Taken together, our study provides insights into metabolic alterations and mitochondrial dysfunction accompanying apoptosis in HepG2 cells upon GP inhibition. Our study can aid in the understanding of the mechanism and development of metabolic inhibitors to treat HCC.

Keywords:  3D tumor spheroids; CP-91149; HCC treatment; cancer metabolism; glycogen; glycogen phosphorylase; glycolysis; metabolomics; pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.bcp.2022.115201
Int J Biol Macromol. 2022 Jul 28. pii: S0141-8130(22)01615-4. [Epub ahead of print]217 878-889

Enzyme-loaded glycogen nanoparticles with tumor-targeting Activatable host-guest supramolecule for augmented chemodynamic therapy.

Fuwei Yang, Wenjie Fang, Meiyang Yang, Weijun Chen, Jiamin Xu, Junze Wang, Wenhua Li, Bingke Zhao, Lipeng Qiu, Jinghua Chen.

  Chemodynamic therapy (CDT) has advantages in site-specific killing tumor and avoiding systemically side effect. Although numerous nano-systems have been developed to enhance the intracellular hydrogen peroxide (H2O2) for improving CDT effect, the biocompatibility of the materials limits their further biomedical applications. Herein glycogen, as a natural biological macromolecule, was used to construct a new targeted separable GOx@GF/HC nanoparticle system to deliver glucose oxidase (GOx) for CDT/starvation tumor therapy. Amination glycogen-ferrocene (GF) as a guest core and hyaluronic acid-β-cyclodextrin (HC) as a host shell were synthesized and self-assembled through host-guest interactions to deliver GOx. After being entered into tumor cells, GOx were released to catalyze glucose to produce gluconic acid and H2O2, which in turn cut off the nutrition of tumor cells for starvation therapy and enhanced the generation of OH with ferrous ion through Fenton reaction. Furthermore, GOx@GF/HC also exhibited remarkable tumor-targeting and tumor-suppression in vivo. Therefore, the GOx@GF/HC system can exert excellent synergistic effect of CDT and starvation therapy on cancer treatment through a cascade reaction, which have some potential application for the development of CDT tumor-treatment.

Keywords:  Chemodynamic therapy; Glycogen; Tumor starvation

DOI:  https://doi.org/10.1016/j.ijbiomac.2022.07.183
Front Physiol. 2022 ;13 975731

Editorial: Insights in exercise physiology: 2021.

Giuseppe D'Antona, Martin Burtscher.



Keywords:  Frontiers; adaptations; challenges; exercise; molecular mechainsm

DOI:  https://doi.org/10.3389/fphys.2022.975731
PeerJ. 2022 ;10 e13713

Blood glucose, insulin and glycogen profiles in Sprague-Dawley rats co-infected with Plasmodium berghei ANKA and Trichinella zimbabwensis.

Pretty Murambiwa, Achasih Quinta Nkemzi, Samson Mukaratirwa.

   Background: Plasmodium falciparum and tissue dwelling helminth parasites are endemic in sub-Saharan Africa (SSA). The geographical overlap in co-infection is a common phenomenon. However, there is continued paucity of information on how the co-infection influence the blood glucose and insulin profiles in the infected host. Animal models are ideal to elucidate effects of co-infection on disease outcomes and hence, blood glucose, insulin and glycogen profiles were assessed in Sprague-Dawley rats co-infected with P. berghei ANKA (Pb) and Trichinella zimbabwensis (Tz), a tissue-dwelling nematode.
Methods: One-hundred-and-sixty-eight male Sprague-Dawley rats (weight range 90-150 g) were randomly divided into four separate experimental groups: Control (n = 42), Pb-infected (n = 42), Tz-infected (n = 42) and Pb- + Tz-infected group (n = 42). Measurement of Pb parasitaemia was done daily throughout the experimental study period for the Pb and the Pb + Tz group. Blood glucose was recorded every third day in all experimental groups throughout the experimental study period. Liver and skeletal muscle samples were harvested, snap frozen for determination of glycogen concentration.
Results: Results showed that Tz mono-infection and Tz + Pb co-infection did not have blood glucose lowering effect in the host as expected. This points to other possible mechanisms through which tissue-dwelling parasites up-regulate the glucose store without decreasing the blood glucose concentration as exhibited by the absence of hypoglycaemia in Tz + Pb co-infection group. Hypoinsulinemia and an increase in liver glycogen content was observed in Tz mono-infection and Tz + Pb co-infection groups of which the triggering mechanism remains unclear.
Conclusions: To get more insights into how glucose, insulin and glycogen profiles are affected during plasmodium-helminths co-infections, further studies are recommended where other tissue-dwelling helminths such as Taenia taeniformis which has strobilocercus as the metacestode in the liver to mimic infections such as hydatid disease in humans are used.

Keywords:  Blood glucose; Co-infection; Insulin; Liver glycogen; Muscle glycogen; Plasmodium berghei; Trichinella zimbabwensis

DOI:  https://doi.org/10.7717/peerj.13713
Ecotoxicol Environ Saf. 2022 Jul 27. pii: S0147-6513(22)00753-9. [Epub ahead of print]242 113913

Glycogen metabolism reprogramming promotes inflammation in coal dust-exposed lung.

Wenyang Wang, Min Mu, Yuanjie Zou, Songsong Deng, Yuting Lu, Qinglong Li, Zeyu Li, Huihui Tao, Yun Wang, Xinrong Tao.

  Long-term coal dust exposure triggers complex inflammatory processes in the coal workers' pneumoconiosis (CWP) lungs. The progress of the inflammation is reported to be affected by disordered cell metabolism. However, the changes in the metabolic reprogramming associated with the pulmonary inflammation induced by the coal dust particles are unknown. Herein, we show that coal dust exposure causes glycogen accumulation and the reprogramming of glucose metabolism in the CWP lung. The glycogen accumulation caused by coal dust is mainly due to macrophages, which reprogram glycogen metabolism and trigger an inflammatory response. In addition, 2-deoxy-D-glucose (2-DG) reduced glycogen content in macrophages, which was accompanied by mitigated inflammation and restrained NF-κB activation. Accordingly, we have pinpointed a novel and crucial metabolic pathway that is an essential regulator of the inflammatory phenotype of coal dust-exposed macrophages. These results shed light on new ways to regulate CWP inflammation.

Keywords:  2-DG; Coal workers’ pneumoconiosis; Glycogen metabolism; Pulmonary inflammation; scMetabolism; scRNA-seq

DOI:  https://doi.org/10.1016/j.ecoenv.2022.113913
Front Aging. 2022 ;3 898853

Targeting Impaired Nutrient Sensing via the Glycogen Synthase Kinase-3 Pathway With Therapeutic Compounds to Prevent or Treat Dementia: A Systematic Review.

Adrian Matysek, Sumudu Perera Kimmantudawage, Lei Feng, Andrea B Maier.

  Background: Dementia is a global challenge with 10 million individuals being diagnosed every year. Currently, there are no established disease-modifying treatments for dementia. Impaired nutrient sensing has been implicated in the pathogenesis of dementia. Compounds that inhibit the glycogen synthase kinase-3 (GSK3) pathway have been investigated as a possible treatment to attenuate the progression of the disease, particularly the suppression of the hyper-phosphorylation process of the tau protein. Aims: Systematically summarizing compounds which have been tested to inhibit the GSK3 pathway to treat cognitive impairment and dementia. Methods: PubMed, Embase and Web of Science databases were searched from inception until 28 July 2021 for articles published in English. Interventional animal studies inhibiting the GSK3 pathway in Alzheimer's disease (AD), Parkinson's dementia, Lewy body dementia, vascular dementia, mild cognitive impairment (MCI) and normal cognitive ageing investigating the change in cognition as the outcome were included. The Systematic Review Centre for Laboratory animal Experimentation's risk of bias tool for animal studies was applied. Results: Out of 4,154 articles, 29 described compounds inhibiting the GSK3 pathway. All studies were based on animal models of MCI, AD or normal cognitive ageing. Thirteen out of 21 natural compounds and five out of nine synthetic compounds tested in MCI and dementia animal models showed an overall positive effect on cognition. No articles reported human studies. The risk of bias was largely unclear. Conclusion: Novel therapeutics involved in the modulation of the GSK3 nutrient sensing pathway have the potential to improve cognitive function. Overall, there is a clear lack of translation from animal models to humans.

Keywords:  Alzheiemer’s disease; aged; ageing; cognition; dementia; glycogen syntase kinase 3; insulin resisitance

DOI:  https://doi.org/10.3389/fragi.2022.898853
BMC Sports Sci Med Rehabil. 2022 Aug 01. 14(1): 149

Prolonged cycling lowers subsequent running mechanical efficiency in collegiate triathletes.

J A Stewart, E K Merritt, D E Lidstone, J M McBride, K A Zwetsloot.

   BACKGROUND: A significant challenge that non-elite collegiate triathletes encounter during competition is the decline in running performance immediately after cycling. Therefore, the purpose of this study was to determine if performing a 40-km bout of cycling immediately before running would negatively influence running economy and mechanical efficiency of running during simulated race conditions in collegiate triathletes.
METHODS: Eight competitive club-level collegiate triathletes randomly performed two trials: cycling for 40 km (Cycle-Run) or running for 5 km (Run-Run), immediately followed by a four-minute running economy and mechanical efficiency of running test at race pace on an instrumented treadmill. Blood lactate, respiratory exchange ratio, mechanical work, energy expenditure, and muscle glycogen were also measured during the four-minute running test.
RESULTS: Mechanical efficiency of running, but not running economy, was significantly lower in Cycle-Run, compared to Run-Run (42.1 ± 2.5% vs. 48.1 ± 2.5%, respectively; p = 0.027). Anaerobic energy expenditure was significantly higher in the Cycle-Run trial, compared to the Run-Run trial (16.3 ± 2.4 vs. 7.6 ± 1.1 kJ; p = 0.004); while net (151.0 ± 12.3 vs. 136.6 ± 9.6 kJ; p = 0.204) and aerobic energy expenditure (134.7 ± 12.3 vs. 129.1 ± 10.5 kJ; p = 0.549) were not statistically different between trials. Analysis of blood lactate, respiratory exchange ratio, mechanical work, and changes in muscle glycogen revealed no statistically significant differences between trials.
CONCLUSIONS: These results suggest that mechanical efficiency of running, but not running economy, is decreased and anaerobic energy expenditure is increased when a 40-km bout of cycling is performed immediately before running in collegiate triathletes.

Keywords:  Energy expenditure; Lactate; Muscle glycogen; Running economy; Work

DOI:  https://doi.org/10.1186/s13102-022-00543-w
J Am Chem Soc. 2022 Aug 02.

1,6-epi-Cyclophellitol Cyclosulfamidate Is a Bona Fide Lysosomal α-Glucosidase Stabilizer for the Treatment of Pompe Disease.

Ken Kok, Chi-Lin Kuo, Rebecca E Katzy, Lindsey T Lelieveld, Liang Wu, Véronique Roig-Zamboni, Gijsbert A van der Marel, Jeroen D C Codée, Gerlind Sulzenbacher, Gideon J Davies, Herman S Overkleeft, Johannes M F G Aerts, Marta Artola.

α-Glucosidase inhibitors are potential therapeutics for the treatment of diabetes, viral infections, and Pompe disease. Herein, we report a 1,6-epi-cyclophellitol cyclosulfamidate as a new class of reversible α-glucosidase inhibitors that displays enzyme inhibitory activity by virtue of its conformational mimicry of the substrate when bound in the Michaelis complex. The α-d-glc-configured cyclophellitol cyclosulfamidate 4 binds in a competitive manner the human lysosomal acid α-glucosidase (GAA), ER α-glucosidases, and, at higher concentrations, intestinal α-glucosidases, displaying an excellent selectivity over the human β-glucosidases GBA and GBA2 and glucosylceramide synthase (GCS). Cyclosulfamidate 4 stabilizes recombinant human GAA (rhGAA, alglucosidase alfa, Myozyme) in cell medium and plasma and facilitates enzyme trafficking to lysosomes. It stabilizes rhGAA more effectively than existing small-molecule chaperones and does so in vitro, in cellulo, and in vivo in zebrafish, thus representing a promising therapeutic alternative to Miglustat for Pompe disease.

DOI: https://doi.org/10.1021/jacs.2c05666