bims-stacyt 2020-10-25 papers

Biochem Biophys Res Commun. 2020 Oct 14. pii: S0006-291X(20)31926-4. [Epub ahead of print]

BDNF secretion from C2C12 cells is enhanced by methionine restriction.

Brain derived neurotrophic factor (BDNF) is produced in skeletal muscle as a myokine that plays a role in muscle metabolism. However, how metabolic changes affect skeletal muscle BDNF expression and release remains to be fully understood. Amino acid restrictions such as methionine restriction (MR) are considered as an alternative fasting approach. Here we reported that in C2C12 myotubes, MR enhanced BDNF release, which was measured using ELISA, RT-qPCR, cell immunostaining, and Western blot. Inhibition of protein transport pathway blocked the MR enhanced BDNF release, confirming that MR-induced BDNF release involved classic protein secretory pathway. MR increased l-lactate product in media, suggesting that MR promoted glycolysis. Treatment with 2-deoxy glucose (2-DG) attenuated lactate production as well as BDNF release, suggesting that glycolysis is involved in the enhanced BDNF release induced by MR. Moreover, treatment with l-Lactate, the end-product of glycolysis, enhanced BDNF gene expression and release in control cells in a dose dependent manner, suggesting lactate produced by glycolysis may mediate the enhanced BDNF release by MR. Overall, the results of this study suggest that MR promotes BDNF secretion from C2C12 myotubes at least partially via enhancing glycolysis and lactate production.

Keywords: Brain derived neurotrophic factor; C2C12; Lactate; Methionine restriction; Myokine

DOI: https://doi.org/10.1016/j.bbrc.2020.10.017

Nanomedicine (Lond). 2020 Oct 23.

Extracellular vesicles in cancer progression: are they part of the problem or part of the solution?

Juliete Nathali Scholl, Camila Kehl Dias, Laurent Muller, Ana Maria Oliveira Battastini, Fabrício Figueiró.

Extracellular vesicles (EVs) are released especially by cancer cells. They modulate the tumor microenvironment by interacting with immune cells while carrying immunosuppressive or immunostimulatory molecules. In this review, we will explore some conflicting reports regarding the immunological outcomes of EVs in cancer progression, in which they might initiate an antitumor immune response or an immunosuppressive response. Concerning immunosuppression, the role of tumor-derived EVs' in the adenosinergic system is underexplored. The enhancement of adenosine (ADO) levels in the tumor microenvironment impairs T-cell function and cytokine release. However, some tumor-derived EVs may deliver immunostimulatory factors, promoting immunogenic activity, even with ADO production. The modulatory role of ADO over the tumor progression represents a piece in an intricate microenvironment with anti and pro tumoral seesaw-like mechanisms.

Keywords: adenosine; cancer; extracellular vesicles; immunology; tumor microenvironment

DOI: https://doi.org/10.2217/nnm-2020-0256

J Leukoc Biol. 2020 Oct 18.

Hypoxia-inducible factors not only regulate but also are myeloid-cell treatment targets.

Lovis Kling, Adrian Schreiber, Kai-Uwe Eckardt, Ralph Kettritz.

Hypoxia describes limited oxygen availability at the cellular level. Myeloid cells are exposed to hypoxia at various bodily sites and even contribute to hypoxia by consuming large amounts of oxygen during respiratory burst. Hypoxia-inducible factors (HIFs) are ubiquitously expressed heterodimeric transcription factors, composed of an oxygen-dependent α and a constitutive β subunit. The stability of HIF-1α and HIF-2α is regulated by oxygen-sensing prolyl-hydroxylases (PHD). HIF-1α and HIF-2α modify the innate immune response and are context dependent. We provide a historic perspective of HIF discovery, discuss the molecular components of the HIF pathway, and how HIF-dependent mechanisms modify myeloid cell functions. HIFs enable myeloid-cell adaptation to hypoxia by up-regulating anaerobic glycolysis. In addition to effects on metabolism, HIFs control chemotaxis, phagocytosis, degranulation, oxidative burst, and apoptosis. HIF-1α enables efficient infection defense by myeloid cells. HIF-2α delays inflammation resolution and decreases antitumor effects by promoting tumor-associated myeloid-cell hibernation. PHDs not only control HIF degradation, but also regulate the crosstalk between innate and adaptive immune cells thereby suppressing autoimmunity. HIF-modifying pharmacologic compounds are entering clinical practice. Current indications include renal anemia and certain cancers. Beneficial and adverse effects on myeloid cells should be considered and could possibly lead to drug repurposing for inflammatory disorders.

Keywords: hypoxia; hypoxia-inducible factor; innate immunity; myeloid cells

DOI: https://doi.org/10.1002/JLB.4RI0820-535R