Qingfang Sun

Neuroprotection and Sensorimotor Functional Improvement by Curcumin after Intracerebral Hemorrhage in Mice

Previous studies revealed that curcumin is neuroprotective in diseases of the central nervous system such as cerebral ischemia and traumatic brain injury. However, the effect of curcumin on intracerebral hemorrhage remains unclear. We, therefore, investigated the pre-clinical effect of curcumin treatment on neurological outcomes following intracerebral hemorrhage, using a mouse model. Intracerebral hemorrhage was induced by autologous blood injection into the right basal ganglia. Curcumin (150 mg/kg) was administered 15 min after intracerebral hemorrhage. Grid walk and neurological scores were evaluated at 1, 3, 7, and 14 days post-injury. Mice were killed at 24 h or 28 days following injury, for histological examination. Evans Blue and water content in the ipsilateral and contralateral hemispheres were measured to evaluate the extent of blood-brain barrier disruption and brain edema. Zonula occludens-1 was detected by immunostaining. In situ zymography was used to measure the localization and focal enzymatic activity of matrix metalloproteinase. Our results demonstrated that curcumin reduced brain edema, measured by alleviated water content and Evans Blue leakage at 24 h (p<0.05). Lateral ventricle measurements indicated that curcumin reduced brain tissue loss in the ipsilateral hemisphere (p<0.05). The same dose of curcumin also significantly attenuated neurological deficits at 1 and 3 days of intracerebral hemorrhage (p<0.05). Immunostaining showed that tight junction continuity around the hematoma was better sustained in curcumin-treated mice than in vehicle-treated mice. At 24 h, the number of matrix metalloproteinase-positive cells was significantly reduced by curcumin (p<0.05). Our study suggests that curcumin ameliorates intracerebral hemorrhage damage by preventing matrix metalloproteinase-mediated blood-brain barrier damage and brain edema, which might provide therapeutic potential for intracerebral hemorrhage.

Curcumin attenuates brain edema in mice with intracerebral hemorrhage through inhibition of AQP4 and AQP9 expression

Aim:Aquaporins (AQPs) are the water-channels that play important roles in brain water homeostasis and in cerebral edema induced by brain injury. In this study we investigated the relationship between AQPs and a neuroprotective agent curcumin that was effective in the treatment of brain edema in mice with intracerebral hemorrhage (ICH).Methods:ICH was induced in mice by autologous blood infusion. The mice immediately received curcumin (75, 150, 300 mg/kg, ip). The Rotarod test scores, brain water content and brain expression of AQPs were measured post ICH. Cultured primary mouse astrocytes were used for in vitro experiments. The expression of AQP1, AQP4 and AQP9 and NF-κB p65 were detected using Western blotting or immunochemistry staining.Results:Curcumin administration dose-dependently reduced the cerebral edema at d 3 post ICH, and significantly attenuated the neurological deficits at d 5 post ICH. Furthermore, curcumin dose-dependently decreased the gene and protein expression of AQP4 and AQP9, but not AQP1 post ICH. Treatment of the cultured astrocytes with Fe2+ (10–100 μmol/L) dose-dependently increased the expression and nuclear translocation of NF-κB p65 and the expression of AQP4 and AQP9, which were partly blocked by co-treatment with curcumin (20 μmol/L) or the NF-κB inhibitor PDTC (10 μmol/L).Conclusion:Curcumin effectively attenuates brain edema in mice with ICH through inhibition of the NF-κB pathway and subsequently the expression of AQP4 and AQP9. Curcumin may serve as a potential therapeutic agent for ICH.

Up-regulation of USP2a and FASN in gliomas correlates strongly with glioma grade

Gliomas are the most common neoplasms in the central nervous system. The lack of efficacy of glioma therapies necessitates in-depth studies of glioma pathology, especially of the underlying molecular mechanisms that transform normal glial cells into tumor cells. Here we report that a deubiquitinating enzyme, ubiquitin-specific protease 2a (USP2a), and its substrate, fatty acid synthase (FASN), are over-expressed in glioma tissue. Using real-time quantitative polymerase chain reaction (PCR), Western blot and immunohistochemistry, we examined the expression and cellular distribution of USP2a and FASN in human glioma tissues. The expression patterns of USP2a and FASN correlated with the pathologic and clinical characteristics of the patients. Real-time PCR analysis showed that the expression levels of USP2a and its substrate FASN were higher in high-grade (World Health Organization [WHO] grades III and IV) glioma tissues than in low-grade (WHO grades I and II) glioma tissues. Western blot analysis indicated that the average optical densitometry ratio of USP2a and its substrate FASN in high-grade gliomas was higher than in low-grade gliomas. Moreover, statistical analysis of grade-classified glioma samples showed that the level of USP2a and FASN expression increased with the elevation of the WHO grade of glioma. USP2a protein expression was detected in the nucleus of glioma tissues and an increase in expression was significantly associated with the elevation of the WHO grade of glioma by immunohistochemistry. These findings expand our understanding of the molecular profiling of glioma and could shed light on new diagnostic criteria for gliomas.

Carvacrol alleviates cerebral edema by modulating AQP4 expression after intracerebral hemorrhage in mice

Carvacrol is a natural compound extracted from many plants of the family Lamiaceae. Previous studies have demonstrated that carvacrol has potential neuroprotective effects in central nervous system diseases such as Alzheimers disease and cerebral ischemia. In this study, we investigated the preclinical effect of carvacrol on cerebral edema after intracerebral hemorrhage (ICH) using a bacterial collagenase-induced ICH mouse model. Mice were randomly divided into sham (n=43), vehicle-treated (n=51), and carvacrol-treated groups (n=101). In carvacrol-treated group, carvacrol was administrated to mice at 0h, 1h, or 3h after ICH induction. Carvacrol was injected intraperitoneally with single doses of 10, 25, 50, or 100mg/kg. Neurologic dysfunctions, brain water content, aquaporins (AQPs) mRNAs level and AQP4 protein expression in the perihematomal area were evaluated post ICH. Our results showed that carvacrol administration improved neurological deficits after day 3 following ICH (p<0.05). Carvacrol reduced cerebral edema and Evans Blue leakage at day 3 (p<0.05). We also found that carvacrol treatment decreased AQP4 mRNA in a dose-dependent manner at 24h. Furthermore, AQP4 protein expression in the perihematomal area was reduced by carvacrol significantly at day 3 after ICH (p<0.05). Our findings suggest that carvacrol may exert its protective effect on ICH injury by ameliorating AQP4-mediated cerebral edema.

Temporal bone chondroblastoma: A review

The objective of this paper was to review temporal bone chondroblastomas in regard to their presentation, radiographic findings, histopathology, and treatment. A case report of a 38‐year‐old man who presented with the left‐sided hearing impairment and temporal swelling was reviewed. A CT scan revealed an osteolytic lobulated expansile mass. MRI depicted two cystic components with fluid–fluid level and enhanced solid mass. Immunohistochemical study of S‐100 was performed using avidin‐biotin‐complex method. The tumor was totally removed, with eroded squamous bone and temporal muscle, via the left zygomatic‐extended middle fossa approach. The pathology of the tumor showed that the tumor cell was spindle‐shaped, along with multinucleated giant cells. These cells had oval to polygonal nuclei; some cells showed grooved nuclei. Intercelluar calcification and hemorrhagic components were also observed in the tumor. Tumor cells were strongly positive for S‐100 protein. Temporal bone chondroblastomas are extremely rare osseous tumors with only 45 cases previously reported in the published literature. They may be confused with more common lesions seen in the temporal bone. Diagnostic radiology, including CT and/or MRI, as well as immunohistochemical staining with S‐100 protein, may assist in making the diagnosis. Treatment is complete surgical excision with preservation of vital neurovascular structures.

Curcumin protects against iron induced neurotoxicity in primary cortical neurons by attenuating necroptosis.

Necroptosis was reported as one backup way of programmed cell death when apoptosis was blocked, and the receptor interacting protein 1 was considered as the key necroptosis regulator protein. Here, we report the neuroprotective effects of curcumin which attenuates necroptosis. Primary cortical neurons were cultured and were injured by ferrous chloride, z.vad.fmk was applied to block apoptosis, curcumin was administrated to protect neurons, necrostatin-1 was applied to inhibit necroptosis if needed. Cell viability was measured by detecting lactate dehydrogenase activity in lysates of surviving cells, and assessed by cell counting kit-8. The expression of receptor interacting protein 1 was detected by immunoblot and immunofluorescence. Results showed that necroptosis mainly occurred in the concentrations of ferrous chloride ranging from 100 to 200μM, curcumin attenuated necroptosis in a dose-dependent manner. Furthermore, curcumin decreased expression of receptor interacting protein 1 in a dose- and time-dependent manner. Taken together, these findings suggest that curcumin protects against iron induced neurotoxicity in primary cortical neurons by attenuating necroptosis.

MicroRNAs-based network: A novel therapeutic agent in pituitary adenoma

Pituitary adenomas are common benign intracranial neoplasms representing about 10-25% of all intracranial neoplasm. Significant morbidity can occur along with pituitary adenomas due to hormonal dysfunction and mass effects. The pathogenesis of pituitary adenoma is unclear, however, etiologic factors include genetic events, hormonal stimulation, and growth factors [1], all of which promote cell proliferation and transformation in the tumor. However, genetic events play the most important role in tumorigenesis. MicroRNAs (miRNAs), a class of non-coding RNAs, not only have function in pituitary cell proliferation and apoptosis but also in neoplastic transformation. It has been shown that miRNAs are differentially expressed in pituitary adenoma when compared with the normal pituitary gland; moreover, miRNAs have been identified as a predictive signature of pituitary adenoma and can be used to predict the histotype. The expression of miRNAs can be used not only to differentiate microadenomas from macroadenomas, but to also distinguish samples of treated patients from samples of non-treated patients. Therefore, we hypothesized that a miRNA-based network may be involved in pituitary tumorigenesis and it can potentially serve as useful diagnostic markers to improve the classification of pituitary adenomas. Here, we reviewed the therapeutic potential that different types of miRNAs may play in tumorigenesis. Moreover, miRNAs may emerge as potential therapeutic targets. We speculated the mechanism of miR-21 is involved in tumorigenesis, leading to improvements in therapies and prevention of metastasis.

Over-expression of tetraspanin 8 in malignant glioma regulates tumor cell progression.

Tumor cell invasion and proliferation remain the overwhelming causes of death for malignant glioma patients. To establish effective therapeutic methods, new targets implied in these processes have to be identified. Tetraspanin 8 (Tspn8) forms complexes with a large variety of trans-membrane and/or cytosolic proteins to regulate several important cellular functions. In the current study, we found that Tspn8 was over-expressed in multiple clinical malignant glioma tissues, and its expression level correlated with the grade of tumors. Tspn8 expression in malignant glioma cells (U251MG and U87MG lines) is important for cell proliferation and migration. siRNA-mediated knockdown of Tspn8 markedly reduced in vitro proliferation and migration of U251MG and U87MG cells. Meanwhile, Tspn8 silencing also increased the sensitivity of temozolomide (TMZ), and significantly increased U251MG or U87MG cell death and apoptosis by TMZ were achieved with Tspn8 knockdown. We observed that Tspn8 formed a complex with activated focal adhesion kinase (FAK) in both human malignant glioma tissues and in above glioma cells. This complexation appeared required for FAK activation, since Tspn8 knockdown inhibited FAK activation in U251MG and U87MG cells. These results provide evidence that Tspn8 contributes to the pathogenesis of glioblastoma probably by promoting proliferation, migration and TMZ-resistance of glioma cells. Therefore, targeting Tspn8 may provide a potential therapeutic intervention for malignant glioma.

Tetraspanin 8-Rictor-Integrin α3 Complex Is Required for Glioma Cell Migration

The malignant glioma remains one of the most aggressive human malignancies with extremely poor prognosis. Glioma cell invasion and migration are the main causes of death. In the current study, we studied the expression and the potential functions of tetraspanin 8 (Tspan8) in malignant gliomas. We found that Tspan8 expression level is high in both malignant glioma tissues and in several human glioma cell lines, where it formed a complex integrin α3 and rictor, the latter is a key component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2). Disruption of this complex, through siRNA-mediated knockdown of anyone of these three proteins, inhibited U251MG glioma cell migration in vitro. We further showed that Tspan8-rictor association appeared required for mTORC2 activation. Knockdown of Tspan8 by the targeted siRNAs prevented mTOR-rictor (mTORC2) assembly as well as phosphorylation of AKT (Ser-473) and protein kinase C α (PKCα) in U251MG cells. Together, these results demonstrate that over-expressed Tspan8 in malignant glioma forms a complex with rictor and integrin α3 to mediate mTORC2 activation and glioma cell migration. Therefore, targeting Tspan8-rictor-integrin α3 complex may provide a potential therapeutic intervention for malignant glioma.

Surgical treatment of brain tumor coexisted with intracranial aneurysm—case series and review of the literature

Coexistence of brain tumor and intracranial aneurysm was previously considered as an uncommon phenomenon. Actually it is not rare in neurosurgical procedures, and its incidence rate may be underestimated. Furthermore, there remains a lack of consensus regarding numerous aspects of its clinical management. We performed a retrospective study of 12 cases of coexistent brain tumor and intracranial aneurysm in our database. Then a systematic PubMed search of English-language literature published between 1970 and 2012 was carried out using the keywords: “brain tumor” and “intracranial aneurysm” in combination with “associate” or “coexist.” A consensus panel of neurosurgeons, anesthetists, interventional neurologists, and intensivests reviewed this information and proposed a treatment strategy. In the majority of patients, clinical symptoms were caused by tumor growth, whereas aneurysm rupture was seen only in a few cases. Meningioma was the commonest tumor associated with aneurysm. In most patients, both lesions occurred within the adjacent area. Treatment of both pathologies in one session was performed in most patients. All of our patients were alive within the period of follow-up. Coexistence of brain tumor and intracranial aneurysm may be a coincidence. The treatment strategy should be designed according to the conditions of tumor and aneurysm, locations of both lesions, and pathologic nature of tumor.