Evidence for the Existence of Secretory Granule (Dense-Core Vesicle)-Based Inositol 1,4,5-Trisphosphate-Dependent Ca2+ Signaling System in Astrocytes

BACKGROUND: The gliotransmitters released from astrocytes are deemed to play key roles in the glial cell-neuron communication for normal function of the brain. The gliotransmitters, such as glutamate, ATP, D-serine, neuropeptide Y, are stored in vesicles of astrocytes and secreted following the inositol 1,4,5-trisphosphate (IP3)-induced intracellular Ca2+ releases. Yet studies on the identity of the IP3-dependent intracellular Ca2+ stores remain virtually unexplored. PRINCIPAL FINDINGS: We have therefore studied the potential existence of the IP3-sensitive intracellular Ca2+ stores in the cytoplasm of astrocytes using human brain tissue samples in contrast to cultured astrocytes that had primarily been used in the past. It was thus found that secretory granule marker proteins chromogranins and secretogranin II localize in the large dense core vesicles of astrocytes, thereby confirming the large dense core vesicles as bona fide secretory granules. Moreover, consistent with the major IP3-dependent intracellular Ca2+ store role of secretory granules in secretory cells, secretory granules of astrocytes also contained all three (types 1, 2, and 3) IP3R isoforms. SIGNIFICANCE: Given that the secretory granule marker proteins chromogranins and secretogranin II are high-capacity, low-affinity Ca2+ storage proteins and chromogranins interact with the IP3Rs to activate the IP3R/Ca2+ channels, i.e., increase both the mean open time and the open probability of the channels, these results imply that secretory granules of astrocytes function as the IP3-sensitive intracellular Ca2+ store

Human microglial cells synthesize albumin in brain

Albumin has been implicated in Alzheimer's disease since it can bind to and transport amyloid beta, the causative agent; albumin is also a potent inhibitor of amyloid beta polymerization. In a pilot phase study of Human Brain Proteome Project, we found evidence that albumin may be synthesized in immortalized human microglial cells, human primary microglial cells, and human fetal and adult brain tissues. We also found the synthesis and secretion is enhanced upon microglial activation by Amyloid [beta]~1-42~, lipopolysaccharide treatment or human Alzheimer's brain

A Role of Canonical Transient Receptor Potential 5 Channel in Neuronal Differentiation from A2B5 Neural Progenitor Cells

Store-operated Ca2+ entry (SOCE) channels are the main pathway of Ca2+ entry in non-excitable cells such as neural progenitor cells (NPCs). However, the role of SOCE channels has not been defined in the neuronal differentiation from NPCs. Here, we show that canonical transient receptor potential channel (TRPC) as SOCE channel influences the induction of the neuronal differentiation of A2B5+ NPCs isolated from postnatal-12-day rat cerebrums. The amplitudes of SOCE were significantly higher in neural cells differentiated from proliferating A2B5+ NPCs and applications of SOCE blockers, 2-aminoethoxy-diphenylborane (2-APB), and ruthenium red (RR), inhibited their rise of SOCE. Among TRPC subtypes (TRPC1-7), marked expression of TRPC5 and TRPC6 with turned-off TRPC1 expression was observed in neuronal cells differentiated from proliferating A2B5+ NPCs. TRPC5 small interfering RNA (siRNA) blocked the neuronal differentiation from A2B5+ NPCs and reduced the rise of SOCE. In contrast, TRPC6 siRNA had no significant effect on the neuronal differentiation from A2B5+ NPCs. These results indicate that calcium regulation by TRPC5 would play a key role as a switch between proliferation and neuronal differentiation from NPCs

Perspective of mesenchymal transformation in glioblastoma.

Despite aggressive multimodal treatment, glioblastoma (GBM), a grade IV primary brain tumor, still portends a poor prognosis with a median overall survival of 12-16 months. The complexity of GBM treatment mainly lies in the inter- and intra-tumoral heterogeneity, which largely contributes to the treatment-refractory and recurrent nature of GBM. By paving the road towards the development of personalized medicine for GBM patients, the cancer genome atlas classification scheme of GBM into distinct transcriptional subtypes has been considered an invaluable approach to overcoming this heterogeneity. Among the identified transcriptional subtypes, the mesenchymal subtype has been found associated with more aggressive, invasive, angiogenic, hypoxic, necrotic, inflammatory, and multitherapy-resistant features than other transcriptional subtypes. Accordingly, mesenchymal GBM patients were found to exhibit worse prognosis than other subtypes when patients with high transcriptional heterogeneity were excluded. Furthermore, identification of the master mesenchymal regulators and their downstream signaling pathways has not only increased our understanding of the complex regulatory transcriptional networks of mesenchymal GBM, but also has generated a list of potent inhibitors for clinical trials. Importantly, the mesenchymal transition of GBM has been found to be tightly associated with treatment-induced phenotypic changes in recurrence. Together, these findings indicate that elucidating the governing and plastic transcriptomic natures of mesenchymal GBM is critical in order to develop novel and selective therapeutic strategies that can improve both patient care and clinical outcomes. Thus, the focus of our review will be on the recent advances in the understanding of the transcriptome of mesenchymal GBM and discuss microenvironmental, metabolic, and treatment-related factors as critical components through which the mesenchymal signature may be acquired. We also take into consideration the transcriptomic plasticity of GBM to discuss the future perspectives in employing selective therapeutic strategies against mesenchymal GBM

Papez Circuit Observed by in vivo Human Brain With 7.0T MRI Super-Resolution Track Density Imaging and Track Tracing

The Papez circuit has been considered as an important anatomical substrate involved in emotional experience. However, the circuit remains difficult to elucidate in the human brain due to the resolution limit of current neuroimaging modalities. In this article, for the first time, we report the direct visualization of the Papez circuit with 7-Tesla super-resolution magnetic resonance tractography. Two healthy, young male subjects (aged 30 and 35 years) were recruited as volunteers following the guidelines of the institutional review board (IRB). Track density imaging (TDI) generation with track tracing was performed using MRtrix software package. With these tools, we were able to visualize the entire Papez circuit. We believe this is the first study to visualize the complete loop of the Papez circuit, including the perforant path (PP), thalamocortical fibers of the anterior nucleus (AN), and mammillothalamic tract (MTT), which were hitherto difficult to visualize by conventional imaging techniques

Primary Diffuse Leptomeningeal Gliomatosis: Report of a Case Presenting with Chronic Meningitis

Neoplastic meningitis occurs in approximately 5% of patients with cancer. Primary diffuse leptomeningeal gliomatosis is a rare condition whereby a glioma arises from heterotopic cell nests in the leptomeninges. We report here a case presenting with clinical features similar to those of chronic infectious meningitis without positive cerebrospinal fluid cytology. Neurological signs in our patient deteriorated progressively without responding to antitubercular, antiviral, or antibiotic therapy. Leptomeningeal biopsy sampling revealed the condition to be primary diffuse leptomeningeal gliomatosis

Little Response of Cerebral Metastasis from Hepatocellular Carcinoma to Any Treatments

Objective : We retrospectively evaluated the survival outcome of patients with brain metastasis from hepatocellular carcinoma (HCC). Methods : Between 1991 and 2007, a total of 20 patients were diagnosed as having brain metastasis from HCC. The mean age of the patients was 55 +/- 13 years, and 17(85.0%) were men. Seventeen (85.0%) patients had already extracranial metastases. The median time from diagnosis of HCC to brain metastasis was 18.5 months. Fourteen (70.0%) patients had stroke-like presentation due to intracerebral hemorrhage (ICH). Ten (50.0%) patients had single or solitary brain metastasis. Among a total of 34 brain lesions, 31 (91.2%) lesions had the hemorrhagic components. Results : The median survival time was 8 weeks (95% Cl, 5.08-10.92), and the actuarial survival rates were 85.0%, 45.0%, 22.5%, and 8.4% at 4, 12, 24, and 54 weeks. Age < 60 years, treatment of the primary and/or extracranial lesions, and recurrent ICH were the possible prognostic factors (p = 0.044, p < 0.001, and p = 0.111, respectively). The median progression-free survival (PFS) time was 3 months (95% Cl, 0.95-5.05). Conclusion : The overall survival of the patients with brain metastasis from HCC was very poor with median survival time being only 8 weeks. However, the younger patients less than 60 years and/or no extracranial metastases seem to be a positive prognostic factor.Choi HJ, 2009, J NEURO-ONCOL, V91, P307, DOI 10.1007/s11060-008-9713-3Kim SR, 2006, WORLD J GASTROENTERO, V12, P6727Seinfeld J, 2006, J NEURO-ONCOL, V76, P93, DOI 10.1007/s11060-005-4175-3Cho DC, 2005, J CLIN NEUROSCI, V12, P699, DOI 10.1016/j.jocn.2004.08.026Chang L, 2004, SURG NEUROL, V62, P172, DOI 10.1016/j.surneu.2003.10.002Del Ben M, 2003, J EXP CLIN CANC RES, V22, P641El-Serag HB, 2002, J CLIN GASTROENTEROL, V35, pS72SALVATI M, 2002, J NEUROSURG SCI, V46, P77McIver JI, 2001, NEUROSURGERY, V49, P447Hayashi K, 2000, SURG NEUROL, V53, P379El-Serag HB, 1999, NEW ENGL J MED, V340, P745Peres MFP, 1998, ARQ NEURO-PSIQUIAT, V56, P658Deuffic S, 1998, LANCET, V351, P214Kim M, 1998, J NEURO-ONCOL, V36, P85TaylorRobinson SD, 1997, LANCET, V350, P1142Gaspar L, 1997, INT J RADIAT ONCOL, V37, P745LUCEY MR, 1997, LIVER TRANSPLANT SUR, V3, P628Murakami K, 1996, NEURORADIOLOGY, V38, pS31PATCHELL RA, 1990, NEW ENGL J MED, V322, P494OTSUKA S, 1987, NEUROL MED CHIR TOKY, V27, P654OKEN MM, 1982, AM J CLIN ONCOL-CANC, V5, P649PUGH RNH, 1973, BRIT J SURG, V60, P646