Microglia and astrocytes mediate synapse engulfment in a MER tyrosine kinase-dependent manner after traumatic brain injury

Recent studies have shown that microglia/macrophages and astrocytes can mediate synaptic phagocytosis through the MER proto-oncokinase in developmental or stroke models,but it is unclear whether the same mechanism is also active in traumatic brain injury.In this study,we established a mouse model of traumatic brain injury and found that both microglia/macrophages and astrocytes phagocytosed synapses and expression of the MER proto-oncokinase increased 14 days after injury.Specific knockout of MER in microglia/macrophages or astrocytes markedly reduced injury volume and greatly improved neurobehavioral function.In addition,in both microglia/macrophages-specific and astrocytes-specific MER knock-out mice,the number of microglia/macrophage and astrocyte phagocytosing synapses was markedly decreased,and the total number of dendritic spines was increased.Our study suggested that MER proto-oncokinase expression in microglia/macrophages and astrocytes may play an important role in synaptic phagocytosis,and inhibiting this process could be a new strategy for treating traumatic brain injury.

Zuo Jin Wan formula inhibits cisplatin-resistance of gastric cancer cells via mitochondrial translocation of cofilin-1

OBJECTIVE Despite the status of cisplatin(DDP) as a classical chemotherapeutic agent in the treatment of cancer,the development of multidrug resistance often leads to a failure of DDP therapy.Traditional Chinese medicine(TCM) as adjuvant chemotherapy of cancer drugs in China has been widely used in cancer treatment.ZuoJin WAN(ZJW),a TCM formula,was proved reversing drug resistance in gastric cancer,but its exact mechanism was still unclear.METHODS CCK-8 assay was used to detect the cell viability.The levels of proteins and mRNA were evaluated using Western blot and q-PCR.Mitochondrial membrane potential was measured by flow cytometry.Depolymerisa.tion of F-actin and translocation of G-actin(gamma-actin) from the cytoplasm to the mitochondria was detected using an immuno fl uorescence assay.RESULTS phosphorylated coflin-1(p-coflin-1) was overexpressed in the DDP-resistant human gastric cancer cell lines SGC7901/DDP and BGC823/DDP,relative to the respective parent cell lines(SGC7901 and BGC823),and DDP induced the dephosphory.lation of p-coflin-1 in both parent lines but not in the DDP-resistant lines.However,ZJW could induce the dephosphorylation of pcoflin-1 and promote coflin-1 translocation from the cytoplasm into the mito.chondria in both SGC7901/DDP and BGC823/DDP cells.This mitochondrial translocation of coflin-1 was found to induce the conversion of flamentous actin to globular-actin,activate mitochondrial dam.age and calcium overloading,and induce the mitochondrial apoptosis pathway.These effects of ZJW on DDP-resistant human gastric cancer cell lines could be reversed via transfection with coflin-1-specifc siRNA,or treatment with a PP1 and PP2A inhibitor.CONCLUSION ZJW can be used as an inhibitor of chemoresistance in gastric cancer,which may partly be due to dephosphorylation of p-coflin-1 via the activation of PP1 and PP2A.

Skp2 is a novel regulator of LSD1 expression and function in gastric cancer

S-phase kinase-associated protein 2(Skp2)is a well-characterized oncoprotein localized mainly in the nucleus and cytoplasm.It is an integral component of SCFskp2 E3 ubiquitin ligase complex which confers substrate selectivity to the ligase by specifically targeting a distinct set of proteins destined for proteasomal degradation such as p21,p27,cyclin E,and c-Myc.1 Skp2 is crucial in a multitude of cellular processes including cell cycle,cell proliferation,apoptosis,differentiation,and survival.However,despite its immense and well-established role in ubiquitin-proteasome system-mediated protein turnover,much is unknown about the function of Skp2 independent of the ubiquitination pathway.Previously,Skp2 has been reported to regulate RhoA gene transcription and the p300 signaling pathway in an E3 ligase-independent manner.2Moreover,Skp2 also acts as a cofactor for c-Myc-regulated gene expression.

Preclinical studies of the triazolo[1,5-a]pyrimidine derivative WS-716 as a highly potent,specific and orally active P-glycoprotein(P-gp)inhibitor

Multidrug resistance(MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein(P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5-a]pyrimidine-based compound WS-716 as a highly potent, specific, and orally active P-gp inhibitor. Through direct binding to P-gp,WS-716 inhibited efflux function of P-gp and specifically reversed P-gp-mediated MDR to paclitaxel(PTX) in multiple resistant cell lines, without changing its expression or subcellular localization. WS-716 and PTX synergistically inhibited formation of colony and 3D spheroid, induced apoptosis and cell cycle arrest at G2/M phase in resistant SW620/Ad300 cells. In addition, WS-716 displayed minimal effect on the drug-metabolizing enzyme cytochrome P4503A4(CYP3A4). Importantly, WS-716 increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo with the T/C value of 29.7% in patient-derived xenograft(PDX) models. Relative to PTX treatment alone, combination of WS-716 and PTX caused no obvious adverse reactions. Taken together, our preclinical studies revealed therapeutic promise of WS-716 against MDR cancer, the promising data warrant its further development for cancer therapy.

MicroRNA-126 is a prospective target for vasculardisease

MicroRNA-126 was involved in angiogenesis during physiological and pathological process. It was mainly expressed in endothelial cells, and defined as a pivotal biological molecule associated with vascular disease. Increased microRNA-126 in endothelial cells promotes angiogenesis in ischemic stroke, repairs impaired endothelial cells in atherosclerosis, and attenuates vascular dysfunction in diabetics. By contrast, microRNA-126 transferred from endothelial cell to smooth muscle cells could lead to proliferation that induced intimal hyperplasia. Additionally, microRNA-126 could be a tumor suppressor or an oncogene, which was depended on the cancer type. In this review, we summarized the function of microRNA-126 in ischemic stroke, atherosclerosis, diabetics, tumor, and discussed the underlying mechanisms.