Activation of SIRT1, an NAD+-dependent deacetylase, prevents retinal ganglion cell (RGC) loss in optic neuritis, an inflammatory demyelinating optic nerve disease. While SIRT1 deacetylates numerous protein targets, downstream mechanisms of SIRT1 activation mediating this neuroprotective effect are unknown. SIRT1 increases mitochondrial function and reduces oxidative stress in muscle and other cells, and oxidative stress occurs in neuronal degeneration. We examined whether SIRT1 activators reduce oxidative stress and promote mitochondrial function in neuronal cells. Oxidative stress, marked by reactive oxygen species (ROS) accumulation, was induced in RGC-5 cells by serum deprivation, or addition of doxorubicin or hydrogen peroxide, and resulted in significant cell loss. SIRT1 activators resveratrol (RSV) and SRTAW04 reduced ROS levels and promoted cell survival in RGC-5 cells as well as primary RGC cultures. Effects were blocked by SIRT1 siRNA. SIRT1 activators also increased expression of succinate dehydrogenase (SDH), a mitochondrial enzyme, and promoted deacetylation of PGC-1α, a co-enzyme involved in mitochondrial function. Results show SIRT1 activators prevent cell loss by reducing oxidative stress and promoting mitochondrial function in a neuronal cell line. Results suggest SIRT1 activators can mediate neuroprotective effects during optic neuritis by these mechanisms, and they have the potential to preserve neurons in other neurodegenerative diseases that involve oxidative stress.

SIRT1 delays RGC loss following traumatic injury. Effects are associated with reduced oxidative stress. Results suggest SIRT1-activating drugs may have a specific role in preventing traumatic optic nerve damage, and suggest a broader role for this strategy in treating a variety of optic neuropathies that may include a component of oxidative stress.

Background Chemotherapy resistance is a primary reason of ovarian cancer therapy failure; hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets. Methods RNA sequencing of cisplatin‐resistant and ‐sensitive (chemoresistant and chemosensitive, respectively) ovarian cancer organoids was performed, followed by detection of the expression level of fibrillin‐1 (FBN1) in organoids and clinical specimens of ovarian cancer. Subsequently, glucose metabolism, angiogenesis, and chemosensitivity were analyzed in structural glycoprotein FBN1‐knockout cisplatin‐resistant ovarian cancer organoids and cell lines. To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer, immunoprecipitation, silver nitrate staining, mass spectrometry, immunofluorescence, Western blotting, and Fӧrster resonance energy transfer‐fluorescence lifetime imaging analyses were performed, followed by in vivo assays using vertebrate model systems of nude mice and zebrafish. Results FBN1 expression was significantly enhanced in cisplatin‐resistant ovarian cancer organoids and tissues, indicating that FBN1 might be a key factor in chemoresistance of ovarian cancer. We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo, which promoted the cisplatin‐resistance of ovarian cancer. Knockout of FBN1 combined with treatment of the antiangiogenic drug apatinib improved the cisplatin‐sensitivity of ovarian cancer cells. Mechanistically, FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) at the Tyr1054 residue, which activated its downstream focal adhesion kinase (FAK)/protein kinase B (PKB or AKT) pathway, induced the phosphorylation of signal transducer and activator of transcription 2 (STAT2) at the tyrosine residue 690 (Tyr690), promoted the nuclear translocation of STAT2, and ultimately altered the expression of genes associated with STAT2‐mediated angiogenesis and glycolysis. Conclusions The FBN1/VEGFR2/STAT2 signaling axis may induce chemoresistance of ovarian cancer cells by participating in the process of glycolysis and angiogenesis. The present study suggested a novel FBN1‐targeted therapy and/or combination of FBN1 inhibition and antiangiogenic drug for treating ovarian cancer.

MicroRNA-506 (miR-506) has been reported to act as a tumor suppressive or an oncogenic miRNA in different types of tumors. However, the roles and underlying molecular mechanism of miR-506 in glioma remain unclear. In the present study, we performed quantitative PCR to investigate the level of miR-506 in 36 pairs of glioma tumor and matched adjacent tissues, and found that miR-506 was downregulated in the glioma tumors compared to the expression in the adjacent normal tissues. Furthermore, a functional assay found that ectopic expression of miR-506 in glioma cells markedly suppressed cell proliferation, colony formation, migration and invasion, and suppressed tumor growth in vivo. Moreover, signal transducer and activator of transcription 3 (STAT3) was identified as a direct target of miR-506. Western blot assay showed that overexpression of miR-506 not only induced changes in STAT3 expression but also altered expression of its downstream genes, including, Bcl2, cyclin D1 and matrix metalloproteinase 2 (MMP-2), in the human glioma cells. In addition, STAT3 mRNA expression was increased in the glioma tissues, and was inversely correlated with miR-506. Importantly, overexpression of STAT3 in glioma cells attenuated the suppressive effects of miR-506 on cell proliferation, colony formation, migration and invasion. These results showed that miR-506 functions as a tumor suppressor in glioma by targeting STAT3, suggesting that miR-506 may serve as a potential target in the treatment of human glioma.

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