Overexpressed ski efficiently promotes neurorestoration, increases neuronal regeneration, and reduces astrogliosis after traumatic brain injury.

Traumatic brain injury (TBI) survivors suffer from long-term disability and neuropsychiatric sequelae due to irreparable brain tissue destruction. However, there are still few efficient therapies to promote neurorestoration in damaged brain tissue. This study aimed to investigate whether the pro-oncogenic gene ski can promote neurorestoration after TBI. We established a ski-overexpressing experimental TBI mouse model using adenovirus-mediated overexpression through immediate injection after injury. Hematoxylin-eosin staining, MRI-based 3D lesion volume reconstruction, neurobehavioral tests, and analyses of neuronal regeneration and astrogliosis were used to assess neurorestorative efficiency. The effects of ski overexpression on the proliferation of cultured immature neurons and astrocytes were evaluated using imaging flow cytometry. The Ski protein level increased in the perilesional region at 3 days post injury. ski overexpression further elevated Ski protein levels up to 14 days post injury. Lesion volume was attenuated by approximately 36-55% after ski overexpression, with better neurobehavioral recovery, more newborn immature and mature neurons, and less astrogliosis in the perilesional region. Imaging flow cytometry results showed that ski overexpression elevated the proliferation rate of immature neurons and reduced the proliferation rate of astrocytes. These results show that ski can be considered a novel neurorestoration-related gene that effectively promotes neurorestoration, facilitates neuronal regeneration, and reduces astrogliosis after TBI.

[Activation of the adenosine A2A receptor at the acute stage of moderate traumatic brain injury enhances the neuroprotective effects of oxaloacetate].

The purpose of the present study was to investigate the effect of glutamate scavenger oxaloacetate (OA) combined with CGS21680, an adenosine A2A receptor (A2AR) agonist, on acute traumatic brain injury (TBI), and to elucidate the underlying mechanisms. C57BL/6J mice were subjected to moderate-level TBI by controlled cortical impact, and then were treated with OA, CGS21680, or OA combined with CGS21680 at acute stage of TBI. At 24 h post TBI, neurological severity score, brain water content, glutamate concentration in cerebrospinal fluid (CSF), mRNA and protein levels of IL-1ß and TNF-α, mRNA level and activity of glutamate oxaloacetate aminotransferase (GOT), and ATP level of brain tissue were detected. The results showed that neurological deficit, brain water content, glutamate concentration in CSF, and the inflammatory cytokine IL-1ß and TNF-α production were exacerbated in CGS21680 treated mice. Administrating OA suppressed the rise of both glutamate concentration in CSF and brain water content, and elevated the ATP level of cerebral tissue. More interestingly, neurological deficit, brain edema, glutamate concentration, IL-1ß and TNF-α levels were ameliorated significantly in mice treated with OA combined with CGS21680. The combined treatment exhibited better therapeutic effects than single OA treatment. We also observed that GOT activity was enhanced in single CGS21680 treatment group, and both the GOT mRNA level and GOT activity were up-regulated in early-stage combined treatment group. These results suggest that A2AR can improve the efficiency of GOT and potentiate the ability of OA to metabolize glutamate. This may be the mechanism that A2AR activation in combination group augmented the neuroprotective effect of OA rather than aggravated the brain damages. Taken together, the present study provides a new insight for the clinical treatment of TBI with A2AR agonists and OA.

High glutamate concentration reverses the inhibitory effect of microglial adenosine 2A receptor on NLRP3 inflammasome assembly and activation.

NLRP3 inflammasome plays a crucial role in the innate immune system. Our group previously reported that the microglial adenosine 2A receptor (A2AR) regulates canonical neuroinflammation, which is affected by the glutamate concentration. However, the regulatory effect of A2AR on NLRP3 inflammasome and the effects of glutamate concentration remain unknown. Therefore, we aimed to investigate the regulatory effect of microglial A2AR on NLRP3 inflammasome assembly and activation as well as the effects of glutamate concentration on the inflammasome assembly and activation. Experiments were conducted on magnetically sorted primary microglia from P14 mice. The results showed that pharmacological A2AR activation ameliorated NLRP3 activation under no or low glutamate concentrations, but this effect was reversed by high glutamate concentrations. Moreover, the mRNA levels of NLRP3 inflammasome-related genes were not affected by A2AR activation or the glutamate concentration. We further demonstrated that A2AR activation inhibited the interaction between NLRP3 and caspase 1 under no or low glutamate concentrations while promoting their interaction under high glutamate concentrations. The oligomerization of ASC also showed a similar trend. In conclusion, our findings proved that the high glutamate concentration could reverse the inhibition of A2AR on NLRP3 inflammasome activation by modulating its assembly, which provides new insights into the regulatory effect of A2AR on neuroinflammation under different pathological conditions.

HMGB1 mediates cognitive impairment caused by the NLRP3 inflammasome in the late stage of traumatic brain injury.

BACKGROUND: Cognitive impairment in the late stage of traumatic brain injury (TBI) is associated with the NOD-, LRR and pyrin domain-containing protein 3 (NLRP3) inflammasome, which plays an important role in neuroinflammation. Although classical inflammatory pathways have been well-documented in the late stage of TBI (4-8 weeks post-injury), the mechanism by which the NLRP3 inflammasome impairs cognition is still unclear. METHODS: Mice lacking the gene encoding for NLRP3 (NLRP3-knockout mice) and their wild-type littermates were used in a controlled cortical impact model of TBI. Levels of NLRP3 inflammasome and inflammatory factors such as IL-1ß and HMGB1 were detected in post-injury hippocampal tissue, as well as long-term potentiation. Behaviors were assessed by T-maze test, novel object recognition, and nesting tests. Glycyrrhizin was used to antagonize HMGB1. Calcium imaging were performed on primary neuronal cultures. RESULTS: By using the NLRP3-knockout TBI model, we found that the continuous activation of the NLRP3 inflammasome and high mobility group box 1 (HMGB1) release were closely related to cognitive impairment. We also found that inhibition of HMGB1 improved LTP reduction and cognitive function by increasing the phosphorylation level of the NMDAR1 subunit at serine 896 while reducing NLRP3 inflammasome activation. CONCLUSION: NLRP3 inflammasome damages memory in the late stage of TBI primarily through HMGB1 upregulation and provides an explanation for the long-term progression of cognitive dysfunction.

NLRP3 Inflammasome-Dependent Increases in High Mobility Group Box 1 Involved in the Cognitive Dysfunction Caused by Tau-Overexpression.

Tau hyperphosphorylation is a characteristic alteration present in a range of neurological conditions, such as traumatic brain injury (TBI) and neurodegenerative diseases. Treatments targeting high-mobility group box protein 1 (HMGB1) induce neuroprotective effects in these neuropathologic conditions. However, little is known about the interactions between hyperphosphorylated tau and HMGB1 in neuroinflammation. We established a model of TBI with controlled cortical impacts (CCIs) and a tau hyperphosphorylation model by injecting the virus encoding human P301S tau in mice, and immunofluorescence, western blotting analysis, and behavioral tests were performed to clarify the interaction between phosphorylated tau (p-tau) and HMGB1 levels. We demonstrated that p-tau and HMGB1 were elevated in the spatial memory-related brain regions in mice with TBI and tau-overexpression. Animals with tau-overexpression also had significantly increased nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation, which manifested as increases in apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), activating caspase-1 and interleukin 1 beta (IL-1ß) levels. In addition, NLRP3-/- mice and the HMGB1 inhibitor, glycyrrhizin, were used to explore therapeutic strategies for diseases with p-tau overexpression. Compared with wild-type (WT) mice with tau-overexpression, downregulation of p-tau and HMGB1 was observed in NLRP3-/- mice, indicating that HMGB1 alterations were NLRP3-dependent. Moreover, treatment with glycyrrhizin at a late stage markedly reduced p-tau levels and improved performance in the Y- and T-mazes and the ability of tau-overexpressing mice to build nests, which revealed improvements in spatial memory and advanced hippocampal function. The findings identified that p-tau has a triggering role in the modulation of neuroinflammation and spatial memory in an NLRP3-dependent manner, and suggest that treatment with HMGB1 inhibitors may be a better therapeutic strategy for tauopathies.

High levels of EphA3 expression are associated with high invasive capacity and poor overall survival in hepatocellular carcinoma.

Although EphA3 expression has been associated with progression or prognosis in several types of tumors, the role of EphA3 in hepatocellular carcinoma (HCC) remains unknown. This study sought to investigate the clinicopathological and prognostic relevance of EphA3 expression in HCC as well as the underlying mechanisms responsible. EphA3 protein was mainly localized within the cytoplasm and at the cell membrane. High EphA3 expression was correlated with tumor size, tumor grade, metastasis, venous invasion and AJCC TNM stage (P<0.05), and patients with high levels of EphA3 expression were at a significantly increased risk for shortened survival time (P<0.05). In vitro, the downregulation of EphA3 expression decreased the invasive capacity of HCC cells via the regulation of VEGF. EphA3 may represent a novel candidate marker for patient prognosis as well a molecular target for HCC therapy.

Gorham-Stout syndrome presenting in a 5-year-old girl with a successful bisphosphonate therapeutic effect.

Gorham-Stout syndrome (GSS), also known as Gorham-Stout disease, massive osteolysis, disappearing bone disease or phantom bone, is a rare disorder of the musculo-skeletal system. It most commonly involves the skull, shoulder and pelvic girdle. Histological examination reveals a progressive osteolysis always associated with an angiomatosis of blood vessels and sometimes of lymphatics, which seemingly is responsible for the destruction of the bone. It is extremely rare that Gorham-Stout syndrome involves the bones of the entire body. A 5-year-old girl complaining of intermittent and dull back pain for 3 months was admitted to a local hospital. X-ray revealed left pleural effusion, and the patient was diagnosed with tuberculous pleurisy. Thus, anti-tuberculosis therapy was performed. However, it was not effective. A soft mass with significant tenderness was found in the upper segment of the right leg 50 days afterwards. X-ray revealed multiple osteolysis of the bilateral clavicle, scapula, rib, vertebral body, ilium, sacrum, femur and tibia. The biopsy from the right tibia disclosed that the lesion was composed of hyperplastic blood vessels and fibrous tissues similar to hemangioma. Based on the above clinical, radiological and histopathological findings, the clinical physician confirmed a diagnosis of Gorham-Stout disease, and prescribed oral anti-osteoclastic medications consisting of bisphosphonates. At present, the girl is alive and healthy, and new lesions have not been noted.

Nanoparticle catalysts with high energy surfaces and enhanced activity synthesized by electrochemical method.

Electrochemical shape-controlled synthesis of metal nanocrystal (NC) catalysts bounded by high-index facets with high surface energy was achieved by developing a square-wave potential route. Tetrahexahedral Pt NCs with 24 {hk0} facets, concave hexoctahedral Pt NCs with 48 {hkl} facets, and multiple twinned Pt nanorods with {hk0} facets were produced. The method was employed also to synthesize successfully trapezohedral Pd NCs with 24 {hkk} facets, and concave hexoctahedral Pd NCs with 48 {hkl} facets. It has been tested that, thanks to the high-index facets with high density of atomic steps and dangling bonds, the tetrahexahedral Pt NCs exhibit much enhanced catalytic activity for equivalent Pt surface areas for electrooxidation of small organic fuels such as ethanol. These results demonstrate that the developed square-wave potential method has surmounted the limit of conventional chemical methods that could synthesize merely metal nanocrystals with low surface energy, and opened a new prospect avenue in shape-controlled synthesis of nanoparticle catalysts with high surface energy and enhanced activity.