Sen Shang,Lin Liu,Xingjuan Wu,Fan Fan,Erling Hu,Leilei Wang,Yan Ding,Yali Zhang,Xiaoyun Lu
The intense and prolonged inflammatory response after ischemic stroke significantly contributes to the secondary neural injury. PI3Kγ, which is involved in the regulation of vascular permeability, chemotactic leukocyte migration and microglia activation, is a key target for intervention in the inflammatory response. In this study, we identified the protective effect of the PI3Kγ inhibitor AS605240 against stroke-related injury in the mouse model of transient intraluminal middle cerebral artery occlusion (tMCAO). The results showed that administration of AS605240 could improve the neurological function score, reduce the infarct size and decrease astrocyte activation in the tMCAO mice after injury. The inhibitory effect of AS605240 on microglia activation is relatively clear. Therefore, in this study, the effects of AS605240 on astrocytes were studied in cell cultures. IL-6 and its soluble receptor were used to construct the astrocyte activation model. AS605240 treatment significantly reduced the astrocyte activation markers and the morphological changes of cells. We also identified 13 inflammatory factors whose expression was significantly upregulated by IL-6/sIL-6R and significantly inhibited by AS605240 at the protein level, and seven of those factors were verified at the mRNA level. These results indicated that specific inhibition of PI3Kγ could reduce astrocyte activation induced by inflammation, which might aid the repair and remodeling of neurons in the later stage after ischemic stroke.
Linna Wang,Xiaoli Wang,Tingting Li,Yihua Zhang,Hui Ji
The inflammatory response mediated by microglia plays a critical role in the progression of ischemic stroke. Phosphoinositide 3-kinase gamma (PI3Kγ) has been implicated in multiple inflammatory and autoimmune diseases, making it a promising target for therapeutic intervention. The aim of this study was to evaluate the efficacy of8e, a hydrogen sulfide (H2S) releasing derivative of 3-n-butylphthalide (NBP), on brain damage and PI3Kγ signaling following cerebral ischemia injury.8esignificantly reduced sensorimotor deficits, focal infarction, brain edema and neural apoptosis at 72 h after transient middle cerebral artery occlusion (tMCAO). The NOX2 isoform of the NADPH oxidase family is considered a major enzymatic source of superoxide. We found that the release of superoxide, together with the expression of NOX2 subunits p47phox, p-p47phox, and the upstream PI3Kγ/AKT signaling were all down-regulated by8e, both in the penumbral region of the rat brain and in the primary cultured microglia subjected to oxygen-glucose deprivation (OGD). With the use of siRNA and pharmacological inhibitors, we further demonstrated that8eregulates the formation of superoxide in activated microglia through the PI3Kγ/AKT/NOX2 signaling pathway and subsequently prevents neuronal death in neighboring neurons. Our experimental data indicate that8eis a potential candidate for the treatment of ischemic stroke and PI3Kγ-mediated neuroinflammation.Keywords:hydrogen sulfide;cerebral ischemia/reperfusion;microglial activation;NOX2;PI3Kγ
Microwave ablation has attracted the most attention as a locoregional therapeutic method for solid neoplasms. However, the high incidence of incomplete ablation that could promote the rapid cancer progression still remains a challenge in clinic. Herein, we found that the high invasiveness of residual tumor following incomplete microwave ablation (iMWA) is mainly due to the myeloid cell-mediated immunosuppression. Accordingly, we develop a biohydrogel scaffold-enabled chemoimmunotherapeutic strategy by targeting myeloid cells with a phosphoinositide 3-kinase γ (PI3Kγ) inhibitor (IPI549) to synergize with immunostimulatory chemotherapy (Oxaliplatin, OX) for post-ablative cancer therapy. With several tumor mouse models, we reveal that OX&IPI549@Gel-based localized chemoimmunotherapy can substantially suppress the growth of tumor post-iMWA, simultaneously evoke robust systemic anticancer immunity to inhibit metastatic spread, and offer strong long-term immunological memory functions against tumor rechallenge. Besides, this work proposes a potential opportunity for precision medicine by utilizing a mechanism-based rationale to the adoption of our pre-existing arsenal of anticancer immunotherapeutic schedule.
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