Glycogen metabolism-mediated intercellular communication in the tumor microenvironment influences liver cancer prognosis

Glycogen metabolism plays a key role in the development of hepatoellular carcinoma(HCC),but the function of glycogen metabolism genes in the tumor microenvironment(TME)is still to be elucidated.Single cell RNA-seq data were obtained from ten HCC tumor samples totaling 64,545 cells and 65 glycogen metabolism genes were analyzed bya nonnegative matrix factorization(NMF).The prognosis and immune response of new glycogen TME cell dusters were predicted by using HCC and immunotherapy cohorts from public databases.HOC single cell analysis was divided into fibroblasts,NT T cells,macrophages,endothelial clls,and B cells,which were separately divided into new cell clusters by glycogen metabolism gene annotation.Pseudo temporal trajectory analysis demonstrated the temporal differentiation trajectory of different glycogen subtype cell dusters.Cellular communication analysis revealed extensive interactions between endothelial cells with glycogen metabolizing TME cell.related subtypes and diferent glycogen subtype cell clusters.SCENIC analysis of transcription factors upstream of TME cell clusters with different glycogen metabolism.In addition,TME cell dusters of glycogen metabolism were found to be enriched in expression in CAF subtypes,CD8 depleted,M1,and M2 types.Bulk seq analysis showed the prognostic signifcance of glycogen metabolism.mediated TME cell dusters in HCC,while a significant immune response was found in the immunotherapy cohort in patients treated with immune checkpoint blockade(ICB),especially for CAFs,T cells,and macrophages In summary,our study reveals for the first time that glycogen metabolism mediates intercellular communication in the hepatocellular carcinoma microenvironment while elucidating the anti-tumor mechanisms and immune prognostic responses of different subtypes of cell dusters.

Maslinic acid modulates glycogen metabolism by enhancing the insulin signaling pathway and inhibiting glycogen phosphorylase

AIM: To investigate the molecular signaling mechanism by which the plant-derived, pentacyclic triterpene maslinic acid(MA) exerts anti-diabetic effects. METHOD: HepG2 cells were stimulated with various concentrations of MA. The effects of MA on glycogen phosphorylase a(GPa) activity and the cellular glycogen content were measured. Western blot analyses were performed with anti-insulin receptor β(IRβ), protein kinase B(also known as Akt), and glycogen synthase kinase-3β(GSK3β) antibodies. Activation status of the insulin pathway was investigated using phospho-IRβ, as well as phospho-Akt, and phospho-GSK3β antibodies. The specific PI3-kinase inhibitor wortmannin was added to the cells to analyze the Akt expression. Enzyme-linked immunosorbent assay(ELISA) was used to measure the effect of MA on IRβ auto-phosphorylation. Furthermore, the effect of MA on glycogen metabolism was investigated in C57BL/6J mice fed with a high-fat diet(HFD). RESULTS: The results showed that MA exerts anti-diabetic effects by increasing glycogen content and inhibiting glycogen phosphorylase activity in HepG2 cells. Furthermore, MA was shown to induce the phosphorylation level of IRβ-subunit, Akt, and GSK3β. The MA-induced activation of Akt appeared to be specific, since it could be blocked by wortmannin. Finally, MA treatment of mice fed with a high-fat diet reduced the model-associated adiposity and insulin resistance, and increased the accumulated hepatic glycogen content. CONCLUSION: The results suggested that maslinic acid modulates glycogen metabolism by enhancing the insulin signaling pathway and inhibiting glycogen phosphorylase.

Glycogen content relative to expression of glycogen phosphorylase(GPH) and hexokinase(HK) during the reproductive cycle in the Fujian Oyster, Crassostrea angulata

Glycogen, a polymer of glucose, is an important means of storing energy. It is degraded by glycogen phosphorylase （GPH） and hexokinase （HK）, glycogen phosphorylase, and hexokinase cDNAs （Ca-GPH and Ca- HK, respectively）, which encode the primary enzymes involved in glycogen use, cloned and characterized and used to investigate the regulation of glycogen metabolism at the mRNA level in Crassostrea angulata. Their expression profiles were examined in different tissues and during different reproductive stages. Full-length cDNA of GPHwas 3 078 bp in length with a 2 607 bp open reading frame （ORF） predicted to encode a protein of 868 amino acids （aa）. The full-length HK cDNA was 3 088 bp long, with an ORF of 1 433 bp, predicted to encode a protein of 505 aa. Expression levels of both genes were found to be significantly higher in the gonads and adductor muscle than in the mantle, gill, and visceral mass. They were especially high in the adductor muscle, which suggested that these oysters can use glycogen to produce a readily available supply of glucose to support adductor muscle activity. The regulation of both genes was also found to be correlated with glycogen content via qRT-PCR and in situ hybridization and was dependent upon the stage of the reproductive cycle （initiation, maturation, ripeness）. In this way, it appears that the expression of Ca-GPH and Ca-HK is driven by the reproductive cycle of the oyster, reflecting the central role played by glycogen in energy use and gametogenic development in C. angulata. It is here suggested that Ca- GPH and Ca-HK can be used as useful molecular markers for identifying the stages of glycogen metabolism and reproduction in C. angulata.

Seasonal Variation of the Glycogen Enzyme Activity in Diploid and Triploid Pacific Oyster Gonad During Sexual Maturation

The glycogen content and the activities of two key enzymes in glycogen metabolism, glycogen phosphorylase and gly- cogen synthetase, in the gonad of diploid and triploid Pacific oysters (Crassostrea gigas) were compared during maturation. The glycogen content in the gonad of diploids decreased with gametogenesis (by 85.7%), but the glycogen content in the gonad of trip- loids did not vary significantly. Activity of glycogen phosphorylase (GP) in the gonad of diploids decreased with gametogenesis (by 55.5%), while GP activity of triploids did not vary significantly during maturation. Activity of glycogen synthetase (GS) in the gonad of diploids increased slightly with gametogenesis, reaching a peak in June. Activity of GS declined sharply from June to July, which might be due to gonad spawning. GS activity of triploid oysters in spawning time (July and August) was significantly higher than that in other months, which might be explained with a ‘compensating’ mechanism for the higher glycogen content in triploids.

Metabolically targeting immunosuppression and immunoescape for future cancer immunotherapy: a narrative review

Cancer immunotherapy has emerged as the most important new approach to cancer treatments and moved rapidly to front-line therapy for certain types of cancers.However,both tumor microenvironments and tumor cells can mediate immunosuppression and immunoescape,thus dampening the efcacy of immunotherapy.Despite the complicacies,mechanistic illuminations of unknown immunosuppression and immunoescape are of paramount importance.This short review highlights the recent important fndings in cancer immunology and immunotherapy,thus providing new insights into cancer immunosuppression,immunoescape and contributing to the design of innovative immunotherapeutics.