Lithium alleviates blood-brain barrier breakdown after cerebral ischemia and reperfusion by upregulating endothelial Wnt/ß-catenin signaling in mice.

Although upregulation of endothelial Wnt/ß-catenin signaling may be used to treat blood-brain barrier (BBB) breakdown caused by cerebral ischemia/reperfusion injury, no agents based on this mechanism are available clinically. Lithium, a medication used for treating bipolar mood disorders, upregulates Wnt/ß-catenin signaling, but whether lithium alleviates BBB breakdown after ischemic stroke by upregulating endothelial Wnt/ß-catenin signaling is unclear. Here, we evaluated the BBB-protective effect of lithium in adult mice with 1-h middle cerebral artery occlusion and 48-h reperfusion (MCAO/R) by determining neurological outcomes, BBB function and related molecular components. Furthermore, we assessed the effect and dependence of lithium on Wnt/ß-catenin signaling in brain microvascular endothelial cells in cell culture and in mice with conditional endothelial knockout of Wnt7 co-receptor Gpr124. Our data show that lithium treatment (3 mmol/kg) significantly decreased infarct volume (34.1 ± 1.8% versus 58.3 ± 2.8% in vehicle controls, P < 0.0001) and improved neurological outcomes of mice following MCAO/R. Importantly, lithium significantly increased BBB integrity shown by reduction of Evans blue leakage (by 45.7%, P = 0.0064) and blood IgG extravasation (by 65.8%, P < 0.0001) into infarcted brain tissue. Mechanistically, lithium upregulated the activity of endothelial Wnt/ß-catenin signaling in vivo and in vitro, increased the protein levels of tight junctions (Claudin-5 and ZO-1), and reduced MMP-9 expression. Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, indicating the protection of lithium on BBB was mainly dependent on the Gpr124-mediated endothelial Wnt/ß-catenin signaling. Taken together, our findings indicate that lithium may serve as a therapeutic candidate for treating the BBB breakdown in the early stage of ischemic stroke following reperfusion therapy.

Molecular characterization of a voltage-gated calcium channel and its potential role in the acaricidal action of scopoletin against Tetranychus cinnabarinus.

The carmine spider mite, Tetranychus cinnabarinus (Boisduval), is a polyphagous agricultural pest with an extensive host plant range. Scopoletin is a promising acaricidal compound whose acaricidal mechanism may occur by disrupting intracellular Ca2+ homeostasis and calcium signaling pathways. However, the underlying mechanism of scopoletin for specific target locations of T. cinnabarinus remains unclear. In this study, a full-length cDNA of the L-type voltage-gated calcium channel (TcLTCC) subunit gene from T. cinnabarinus was cloned and characterized. The expression pattern of the TcLTCC gene in all developmental stages of T. cinnabarinus was analyzed. The gene was highly expressed in larval and nymphal stages and was significantly upregulated after treatment with scopoletin. Knocking down the TcLTCC transcript reduced the sensitivity of T. cinnabarinus to scopoletin. Homology modeling and molecular docking were also conducted. The interaction between scopoletin and TcLTCC showed that scopoletin inserted into the cavity bound to the site of the TcLTCC protein by the driving force of hydrogen bonding. This study provides insights into the mechanism by which scopoletin interacts with TcLTCC. Results can improve the understanding of the toxicity of scopoletin to T. cinnabarinus and provide valuable information for the design of new LTCC inhibitors.

Acaricidal Mechanism of Scopoletin Against Tetranychus cinnabarinus.

Scopoletin is a promising acaricidal botanical natural compound against Tetranychus cinnabarinus, and its acaricidal mechanism maybe involve calcium overload according to our previous study. To seek potential candidate target genes of calcium overload induced by scopoletin in T. cinnabarinus, RNA-seq was utilized to detect changes in transcription levels. 24 and 48 h after treatment, 70 and 102 differentially expressed genes were obtained, respectively. Target genes included 3 signal transduction genes, 4 cell apoptosis genes, 4 energy metabolism genes, and 2 transcription factor genes. The role of 3 calcium signaling pathway-related genes, namely, G-protein-coupled neuropeptide receptor, Bcl-2 protein and guanylate kinase (designated TcGPCR, TcBAG, and TcGUK, respectively) in the calcium overload were investigated in this study. RT-qPCR detection showed that scopoletin treatment upregulated the expression level of TcGPCR and downregulated the expression level of TcBAG and TcGUK. The result of RNAi indicated that downregulation of TcGPCR decreased susceptibility to scopoletin, and downregulation of TcBAG and TcGUK enhanced susceptibility to scopoletin. Functional expression in Chinese hamster ovary cells showed that scopoletin induced a significant increase in intracellular free calcium [Ca2+]i levels by activating TcGPCR. These results demonstrated that the acaricidal mechanism of scopoletin was via disrupting intracellular Ca2+ homeostasis and calcium signaling pathway mediated by GPCR, BAG, and GUK.

A novel small-molecule activator of Sirtuin-1 induces autophagic cell death/mitophagy as a potential therapeutic strategy in glioblastoma.

Sirtuin-1 (SIRT1), the mammalian ortholog of yeast Sir2p, is well known to be a highly conserved NAD+-dependent protein deacetylase that has been emerging as a key cancer target. Autophagy, an evolutionarily conserved, multi-step lysosomal degradation process, has been implicated in cancer. Accumulating evidence has recently revealed that SIRT1 may act as a tumor suppressor in several types of cancer, and thus activating SIRT1 would represent a possible therapeutic strategy. Thus, in our study, we identified that SIRT1 was a key prognostic factor in brain cancer based upon The Cancer Genome Atlas and tissue microarray analyses. Subsequently, we screened a series of potential small-molecule activators of SIRT1 from Drugbank, and found the best candidate compound F0911-7667 (hereafter, named Comp 5), which showed a good deacetylase activity for SIRT1 rather than other Sirtuins. In addition, we demonstrated that Comp 5-induced autophagic cell death via the AMPK-mTOR-ULK complex in U87MG and T98G cells. Interestingly, Comp 5-induced mitophagy by the SIRT1-PINK1-Parkin pathway. Further iTRAQ-based proteomics analyses revealed that Comp 5 could induce autophagy/mitophagy by downregulating 14-3-3γ, catalase, profilin-1, and HSP90α. Moreover, we showed that Comp 5 had a therapeutic potential on glioblastoma (GBM) and induced autophagy/mitophagy by activating SIRT1 in vivo. Together, these results demonstrate a novel small-molecule activator of SIRT1 that induces autophagic cell death/mitophagy in GBM cells, which would be utilized to exploit this compound as a leading drug for future cancer therapy.

Repeated Peritoneal Catheter Blockage Caused by Neurocysticercosis Following Ventriculoperitoneal Shunt Placement for Hydrocephalus.

Cerebral cysticercosis is common, but the possibility for repeated occurrence of peritoneal catheter blockage caused by neurocysticercosis (NCC) after two revisions following ventriculoperitoneal shunt placement for hydrocephalus is unusual. Herein, we describe one rare case in which peritoneal catheter revision was performed two times unsuccessfully. Endoscopic cysternostomy rather than peritoneal catheter adjustment was performed successfully, and histopathological examination of excised cystic samples confirmed NCC in our hospital. The present case highlights the need for awareness of NCC as a possible etiology of hydrocephalus, especially in developing countries. Uncommon findings in both lateral ventricles following low-field magnetic resonance imaging scans as well as the rarity of this infection involved in unusual location play important roles in misdiagnosis and incorrect treatment for hydrocephalus; thus, endoscopic cysternostomy, rather than multiple shunt adjustment of the peritoneal end, is recommended in the selected patient. To the best of our knowledge, this is the first report describing the misdiagnosis and inappropriate treatment of hydrocephalus caused by cerebral cysticercosis in China.

Silencing Chitinase Genes Increases Susceptibility of Tetranychus cinnabarinus (Boisduval) to Scopoletin.

The carmine spider mite Tetranychus cinnabarinus is a major pest of crop and vegetable plants worldwide. Previous studies have shown that scopoletin is a promising acaricidal compound against Tetranychus cinnabarinus. However, the acaricidal mechanism of scopoletin remains unclear. In the present study, 12 full-length cDNAs of chitinase (CHIT) genes from Tetranychus cinnabarinus (designated TcCHITs) were cloned and characterized. Although TcCHITs were expressed throughout all life stages, their expression levels were significantly upregulated during the larval and nymphal stages. TcCHITs were downregulated 24 h after treatment with scopoletin and upregulated 24 h after treatment with diflubenzuron (DFB, a chitin synthesis inhibitor). Feeding double-stranded RNA effectively silenced TcCHIT transcription in Tetranychus cinnabarinus, thus increasing its susceptibility to scopoletin but reducing that to DFB. Meanwhile, TcCHIT silencing in larvae and adult resulted in an extremely low molting rate (7.3%) and high mortality rate (53.3%), respectively, compared with those in the control group. CHIT genes are closely related to arthropod survival, molting, and development in Tetranychus cinnabarinus, suggesting that acaricidal mechanisms of scopoletin and DFB may occur by inhibition and activation of CHIT gene expression, respectively. TcCHIT constitutes a possible target of scopoletin and DFB in Tetranychus cinnabarinus.

[Industrial ecological development of Jilin Province, Northeast China based on structure optimization vision.] / 基于结构调整视角的吉林省产业生态化发展.

Based on the interactive coercing mechanism between the industrial system and the ecosystem, we evaluated Jilin's ecologicalization of industrial structure, employing the systematic ana-lysis method and the comprehensive index evaluation method, and explored the spatio-temporal cha-racteristics.The result showed that the ecological level of industrial structure as well as the industrial structure optimization and resource-environmental efficiency had been significantly improved in 2000-2013. The regional difference showed a trend of resource-environmental efficiency > industrial structure optimization > ecologicalization of industrial structure. Spatially, it demonstrated a "higher in west, lower in east" pattern, and at city scale, it showed a decreasing trend from the core (Changchun) to outside. According to the coordination of industrial structure optimization and resource-environmental efficiency, we categorized the nine cities in Jilin Province into four ecologica-lization types: high coordination type, low coordination type, economic development ahead, and ecological development ahead.

Intracranial inflammatory granuloma caused by toxoplasmosis.

Toxoplasmosis is a serous parasitic zoonosis caused by the protozoan Toxoplasma gondii worldwide. Human beings acquire the disease by eating infected meat containing T. gondii cysts, by ingesting water or vegetables contaminated with oocysts shed in the feces of an infected cat, and by transmission from mother to fetus. Cerebral toxoplasmosis is one of the most serious complications in immunocompromised individuals such as HIV-infected patients, with a high mortality rate, whereas the incidence of cerebral toxoplasmosis is extremely rare in immunocompetent persons. Due to the low incidence and the high rate of misdiagnosis, cerebral toxoplasmosis was occasionally described in sporadic cases. (1) Furthermore, the diagnosis of cerebral toxoplasmosis is rather difficult because the clinical manifestations are non-specific and are not sufficiently characteristic for a definite diagnosis. It mimics several other infectious diseases or primary central nervous system (CNS) tumor. (2) In the present study, we reported an exceedingly rare cerebral toxoplasmosis with obvious space-occupying lesion occurring in the left temporal lobe of an immunocompetent adult patient. To our knowledge, this is the first report of successful treatment of acquired cerebral toxoplasmosis in China.

[Clinical features and microsurgical management of rare tumors in the sellar region].

OBJECTIVE: To investigate the clinical characteristics and microsurgical managements of rare tumors in the sellar region. METHODS: Six rare cases of tumors in the sellar region treated by microsurgery from Jan 2000 to Jan 2010 were reviewed retrospectively. Subsequent treatments were according to the status of preoperative alpha fetal protein (AFP) and human chorionic gonadotropin (HCG) measurement as well as confirmed by histopathological examination in all six patients. RESULTS: Total resection of the tumor was achieved in 2 cases and subtotal resection in 4 cases. Postoperative histopathology confirmed that the lesions were tumors in 5 cases and fungal pseudotumor in 1 case. Moreover, variety of histological types were observed in the present series, including leiomyosarcoma, malignant yolk sac tumor, mixed germ cell tumor, embryonal carcinoma, pilocytic astrocytoma and fungal pseudotumor, respectively. The serum levels of AFP and HCG were elevated to some extent in the patients with malignant yolk sac tumor, mixed germ cell tumor or embryonal carcinoma. Follow-up was conducted in all patients for 1 month to 3 years. The patients with malignant yolk sac tumor and embryonal carcinoma as well as leiomyosarcoma died in 5, 6, 10 months after operation, respectively. Subarachnoid hemorrhage occurred in the case of fungal pseudotumor at 2 months after surgery. The other two patients were surviving well. CONCLUSIONS: Rare non-germinomatous malignant germ cell tumors are predominantly susceptible to the sellar region. Furthermore, High misdiagnosis rate and poor prognosis are characteristic in the present study. Dynamic AFP and HCG detection may play an important role in the diagnosis of those non-germinomatous malignant germ cell tumors located in the sellar region. The importance of awareness of the presence of such rare lesions in the sellar region is emphasized.

Microsurgical resection of craniopharyngioma of the third ventricle via an improved transventricular approach.

BACKGROUND: Craniopharyngioma of the third ventricle is difficult to treat and its therapeutic regimens and operative approaches have been controversial. This study was undertaken to probe indications for microsurgical resection of craniopharyngioma of the third ventricle via an improved transventricular approach, its surgical procedures and therapeutic effects, and prevention of postoperative complications. METHODS: Fifty-one patients with craniopharyngioma of the third ventricle were treated from January 2000 to October 2004 by an improved transventricular approach for removing the tumor via the interventricular foramen, the intermedius of the septum pellucidum or choroid fissure. Symptoms and signs of the patients, and results of imaging, operation, and follow-up were analyzed. RESULTS: Of the 51 patients who had received the improved transventricular resection, 4 underwent a combined approach with an entrance of the pterion. Forty patients (78.43%) underwent total resection and others subtotal resection, without an operative death. Epileptic seizures were found in 3 patients (5.88%) and subdural effusion in the operative field in 4 (7.84%). All patients showed good general conditions after operation, and follow-up for an average of 27.52 months showed relapse of the tumour in 8 patients (15.69%). CONCLUSIONS: Microsurgical resection of craniopharyngioma of the third ventricle by an improved transventricular approach has advantages of operative safety and efficacy, lower mortality and disability, and less complications.