Sirtuin-1 (SIRT1), the mammalian ortholog of yeast Sir2p, is well known to be a highly conserved NAD+-dependent protein deacetylase that has been emerging as a key cancer target. Autophagy, an evolutionarily conserved, multi-step lysosomal degradation process, has been implicated in cancer. Accumulating evidence has recently revealed that SIRT1 may act as a tumor suppressor in several types of cancer, and thus activating SIRT1 would represent a possible therapeutic strategy. Thus, in our study, we identified that SIRT1 was a key prognostic factor in brain cancer based upon The Cancer Genome Atlas and tissue microarray analyses. Subsequently, we screened a series of potential small-molecule activators of SIRT1 from Drugbank, and found the best candidate compound F0911-7667 (hereafter, named Comp 5), which showed a good deacetylase activity for SIRT1 rather than other Sirtuins. In addition, we demonstrated that Comp 5-induced autophagic cell death via the AMPK-mTOR-ULK complex in U87MG and T98G cells. Interestingly, Comp 5-induced mitophagy by the SIRT1–PINK1–Parkin pathway. Further iTRAQ-based proteomics analyses revealed that Comp 5 could induce autophagy/mitophagy by downregulating 14-3-3γ, catalase, profilin-1, and HSP90α. Moreover, we showed that Comp 5 had a therapeutic potential on glioblastoma (GBM) and induced autophagy/mitophagy by activating SIRT1 in vivo. Together, these results demonstrate a novel small-molecule activator of SIRT1 that induces autophagic cell death/mitophagy in GBM cells, which would be utilized to exploit this compound as a leading drug for future cancer therapy.

Intracerebral hemorrhage (ICH) remains a devastating type of stroke that lacks an effective treatment. Recent evidence has demonstrated that CCL2 is involved in the blood‐brain barrier (BBB) disruption and propagermanium (PG) as a CCL2 receptor inhibitor is neuroprotective in ischemic stroke. However, whether PG therapy exert effective role in acute ICH still unclear. In this study, our goal was to investigate the potential role of CCL2 and the effects of PG in ICH. Differentially expressed RNAs including CCL2 were detected in human ICH. CCL2 and the activation of p‐p38 MAPK and AQP4 expression were analyzed in rats after ICH. Brain water content and BBB integrity as well as neurological function were also examined after PG administration. In addition, the mechanism by which CCL2‐mediated BBB injury was further investigated by cell coculture. Our findings showed that PG could effectively reduce brain edema and improve neurobehavioral functions. p‐p38 MAPK and AQP4 expression were significantly inhibited by PG in vivo and in vitro. To the best of our knowledge, this is the first demonstration of PG in neuroprotecting the BBB integrity by inhibition of CCL2‐CCR2‐p38 MAPK pathway following ICH, targeting CCL2 could be developed as a novel treatment for hemorrhagic stroke.

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Carbonic anhydrase-1 (CA-1) is a metalloenzyme present at high concentrations in erythrocytes. Our previous studies showed that erythrocyte lysis contributes to brain edema formation after intracerebral hemorrhage (ICH) and a recent study indicates that CA-1 can cause blood-brain barrier disruption. The present study investigated the role of CA-1 in ICH-induced brain injury. There were three groups in the study. In the first, adult male Sprague-Dawley rats received 100 μl autologous blood injection into the right caudate. Sham rats had a needle insertion. Rat brains were used for brain CA-1 level determination. In the second group, rats received an intracaudate injection of either 50 μl CA-1 (1 μg/μl) or saline. Brain water content, microglia activation and neuronal death (Fluoro-Jade C staining) were examined 24 hours later. In the third group, acetazolamide (AZA, 5 μl, 1 mM), an inhibitor of carbonic anhydrases, or vehicle was co-injected with 100 μl blood. Brain water content, neuronal death and behavioral deficits were measured. We found that CA-I levels were elevated in the ipsilateral basal ganglia at 24 hours after ICH. Intracaudate injection of CA-1 induced brain edema (79.0 ± 0.6 vs. 78.0±0.2% in saline group, p<0.01), microglia activation and neuronal death (p<0.01) at 24 hours. AZA, an inhibitor of CA, reduced ICH-induced brain water content (79.3 ± 0.7 vs. 81.0 ± 1.0% in the vehicle-treated group, p<0.05), neuronal death and improved functional outcome (p<0.05). These results suggest that CA-1 from erythrocyte lysis contributes to brain injury after ICH.

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