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Clinical studies have demonstrated that decreased adiponectin is associated with the development of Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD). We focused on determining the neuroprotective effect offered by adiponectin against streptozotocin-induced brain damage in ICV-STZ rat model. We found that adiponectin supplements significantly restored the cognitive deficits in ICV-STZ rat model including shorter escape latency, more crossing times and increased time spent in the target quadrant. Adiponectin supplements also increased number of dendritic branches and mushroom percentage. In addition, adiponectin supplements attenuated tau hyperphosphorylation at multiple AD-related sites through activation of protein Ser9-phosphorylated glycogen synthase kinase-3β (Ser9-GSK-3β) with increased the Akt and PI3K activity. Our data suggest that adiponectin supplements have neuroprotective effects on the ICV-STZ rat model, which may be mediated by the activation of the PI3K/Akt/GSK-3β signaling pathway. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) leads to severe and long-lasting neurological disability. Presently, the lack of effective therapies for SCI is largely attributable to an incomplete understanding of its pathogenesis. F-box and WD repeat domain-containing protein 7 (FBW7, also known as FBXW7) is a type of E3 ubiquitin ligase complex, and plays essential roles in regulating different pathological and physiological processes. In this study, we attempted to explore the effects of FBW7 on SCI progression by the in vivo and in vitro experiments. SCI mice showed significantly reduced expression of FBW7 in spinal cord tissues. Promoting FBW7 expression via intrathecal injection of AAV9/FBW7 effectively improved locomotor function in SCI mice. Neuronal death in spinal cords of SCI mice was obviously ameliorated by FBW7 over-expression, along with greatly decreased expression of cleaved Caspase-3. In addition, microglial activation in spinal cord specimens was detected in SCI mice through increasing Iba-1 expression levels, which was, however, attenuated in SCI mice injected with AAV9/FBW7. Additionally, FBW7 over-expression dramatically restrained inflammatory response in spinal cord tissues of SCI mice, as evidenced by the down-regulated expression of tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) through blocking the activation of nuclear factor-κB (NF-κB) signaling. These anti-inflammatory effects of FBW7 were confirmed in LPS-stimulated mouse microglial BV2 cells. Finally, our in vitro studies showed that conditional medium (CM) collected from LPS-incubated BV2 cells markedly induced apoptosis in the isolated primary spinal neurons; However, this effect was overtly ameliorated by CM from LPS-exposed BV2 cells over-expressing FBW7. Thus, FBW7-regulated inflammation in microglial cells was involved in the amelioration of neuronal apoptosis during SCI development. Collectively, these findings illustrated that FBW7 expression was down-regulated in spinal cords of SCI mice, and promoting its expression could effectively mitigate SCI progression by repressing microglial inflammation and neuronal death. • FBW7 protects mice against SCI in mice. • FBW7 up-regulation alleviates inflammation in SCI mice and in LPS-treated microglial cells. • FBW7 increase alleviates neuronal apoptosis stimulated by LPS. [ABSTRACT FROM AUTHOR]

In various cancers, abnormal USP9X expression is involved in tumorigenesis, progression, apoptosis, and metastasis. However, the relationship between USP9X abnormal expression and cisplatin resistance in nasopharyngeal carcinoma (NPC) cells remains unclear. Using qRT-PCR and western blot, we detected the expressions of USP9X and β-catenin in NPC cells. The effects of USP9X on cisplatin resistance, proliferation, apoptosis, and metastasis were examined by CCK-8 assay, flow cytometry, wound-healing assay, and Transwell chamber assay. Co-IP assay, qRT-PCR, and western blot were performed to explore the detailed molecular mechanism of USP9X-β-catenin and its effect on the protein levels of MDR1, MRP2, Bcl-2, Bax, MMP2, and MMP9. We found that USP9X and β-catenin expressions in cisplatin-resistant cell lines (HNE1/DDP) were much higher than cisplatin-sensitive cell lines (HNE1) at both mRNA and protein levels. Co-IP assay demonstrated that USP9X was immunoprecipitated with β-catenin in NPC cells. Knockdown of USP9X was able to partially reverse cisplatin resistance, increased cisplatin-induced apoptosis, and decreased the capacities of proliferation, migration, and invasion. Overexpression of USP9X can increase cisplatin resistance in NPC cells. Moreover, knockdown of USP9X expression can significantly reduce the expressions of MDR1, MRP2, Bcl-2, MMP2, and MMP9, but significantly increased the expression of Bax. These findings indicate that USP9X high expression plays a significant part in cisplatin resistance of NPC. This study elucidated the possible mechanism of cisplatin resistance in NPC cells and may have implications for the therapeutic reversal of cisplatin resistance.

Acute lung injury (ALI) is a common emergency and severe case in clinic. High mobility group protein box 1 (HMGB1) can be treated as a new anti-inflammatory treatment target. Toll-like receptor 4 (TLR4) is an important receptor of HMGB1. Ketamine is a widely used intravenous anesthetic with good anti-inflammatory and immune regulating function. Whether it can protect ALI through inhibiting HMGB1 and TLR4 expression in lung tissue still needs further investigation. Male SD rats were randomly divided into control, lipopolysaccharide (LPS) group and ketamine intervention group with 15 rats in each group. The rats were euthanatized at 24 h after modeling and the bronchoalveolar lavage fluid (BALF) was collected for HMGB1 and TLR4 level detection. Western Blot was applied to analyze HMGB1 and TLR4 protein expression in the lung tissue. HMGB1 and TLR4 concentration in BALF were 5.369 ± 1.564 ng/ml and 43.980 ± 7.524 pg/ml in the control, respectively. They were 12.358 ± 4.681 ng/ml and 102.538 ± 8.412 pg/ml in LPS group, and 7.399 ± 2.346 ng/ml and 87.208 ± 7.558 pg/ml in ketamine intervention group, respectively. Their levels increased significantly in LPS group and down-regulated after ketamine intervention. HMGB1 and TLR4 protein expression in lung tissue elevated obviously in LPS group, and decreased after ketamine treatment. HMGB1 and TLR4 protein level showed positive correlation in lung tissue (r = 0.921, P < 0.001). Ketamine can inhibit HMGB1 and TLR4 expression in ALI, and alleviate LPS induced rat lung injury.