bims-stacyt 2018-06-24 papers

Biol Chem. 2018 Jun 19. pii: /j/bchm.ahead-of-print/hsz-2018-0173/hsz-2018-0173.xml. [Epub ahead of print]

Hypoxia due to rapid tumor growth with impaired neovascularization and inflammation resulting from immune cell activation are hallmarks of cancer. Hypoxia-inducible factors control transcriptional adaptation in response to low oxygen conditions, both in tumor and immune cells. In addition, sphingolipids become increasingly recognized as important cell mediators in tumor and inflammatory hypoxia. Recent studies have identified acid sphingomyelinase (ASM), a central enzyme in the sphingolipid metabolism, as a regulator of several types of stress stimuli pathways and an important player in the tumor microenvironment. Therefore, this review will address the connection between the hypoxic response and the ASM/ceramide system in the context of inflammatory hypoxia.

Keywords: acid sphingomyelinase; ceramide; hypoxia-inducible factor; tumor hypoxia

DOI: https://doi.org/10.1515/hsz-2018-0173

Biochem Biophys Res Commun. 2018 Jun 16. pii: S0006-291X(18)31370-6. [Epub ahead of print]

MIF protects against oxygen-glucose deprivation-induced ototoxicity in HEI-OC1 cochlear cells by enhancement of Akt-Nrf2-HO-1 pathway.

Wen-Yan Zhu, Xin Jin, Yong-Chi Ma, Zhi-Biao Liu.

Ischemia and oxidative stress play crucial roles in the pathophysiology of sudden sensorineural hearing loss (SSNHL). Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine and serves an important role in hearing function. The present study was designed to evaluate the effect of MIF on oxygen-glucose deprivation (OGD)-induced ototoxicity and to elucidate its molecular mechanism. In HEI-OC1 auditory cells, OGD reduced cell viability and increased supernatant lactate dehydrogenase (LDH) and MIF in a time-dependent manner. However, the reduced cell viability exerted by OGD was attenuated by antioxidant and MIF. Luciferase reporter assay demonstrated that MIF could activate NF-E2-related factor 2 (Nrf2), and real-time PCR showed increased mRNA expressions of Nrf2 and two Nrf2-responsive genes, including heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). MIF also suppressed oxidative stress induced by OGD, as demonstrated by decreased MDA and increased GSH in cellular supernatant. Inhibition of Nrf2 using siRNA suppressed HO-1 protein expression, the protective effect on OGD-induced injury and decrease in oxidative stress by MIF. Moreover, MIF prevented OGD-induced reduction of Akt1 phosphorylation at Ser473. LY294002, an inhibitor of PI3K/Akt signaling, attenuated the enhancement of Nrf2 protein and protective effect of MIF in OGD-treated cochlear cells. We demonstrate that MIF protects cochlear cells against OGD-induced injury through activation of Akt-Nrf2-HO-1 pathway.

Keywords: Cochlear cell; Macrophage migration inhibitory factor (MIF); NF-E2-related factor 2 (Nrf2); Oxidative stress; Oxygen-glucose deprivation (OGD)

DOI: https://doi.org/10.1016/j.bbrc.2018.06.058

Pharmacol Ther. 2018 Jun 19. pii: S0163-7258(18)30105-0. [Epub ahead of print]

Glycosylation as new pharmacological strategies for diseases associated with excessive angiogenesis.

Simon Bousseau, Luisa Vergori, Raffaella Soleti, Guy Lenaers, M Carmen Martinez, Ramaroson Andriantsitohaina.

Angiogenesis is a complex process describing the growth of new blood vessels from existing vasculature, and is triggered by local pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), which increase the metabolism of endothelial cells (ECs). Angiogenesis takes part in various physiological conditions such as embryogenesis, placental growth, and in pathological conditions such as tumor growth, diabetic retinopathy, rheumatoid arthritis (RA) and ischemic diseases. Current therapies against excessive angiogenesis target vascular growth signaling. However, tumors often counteract these therapies through adaptive mechanisms, thus novel alternative anti-angiogenic strategies are needed. Targeting metabolism is a new anti-angiogenic paradigm, especially through the inhibition of energy metabolism and glycosylation, with the perspective of maintaining the delicate balance between the beneficial and deleterious effects of excessive angiogenesis in patients. Recent studies described a role for EC glycolysis and its main regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the regulation of angiogenesis, but only few studies are related to the role of the hexosamine biosynthesis pathway during angiogenesis. Glycosylation allows the formation of glycoproteins, glycolipids and proteoglycans and impacts many pathways. The addition of glycans to N-linked proteins is catalyzed by the enzymatic activity of N-acetylglucosaminyltransferases (GnTs), which regulates the glycosylation status of key angiogenic factors such as VEGF receptor 2 (VEGFR2) and Notch. In addition, glycan-galectin (Gal) interactions regulate vascular signaling programs and may contribute to tumor adaptations to anti-angiogenic strategies. Herein, we review novel pharmacological strategies targeting glycosylation, which could be used to decrease excessive angiogenesis in pathological conditions.

Keywords: Angiogenesis; Cancer growth; Endothelial metabolism; Glycosylation; Lymphangiogenesis; Pharmacotherapy

DOI: https://doi.org/10.1016/j.pharmthera.2018.06.003