Thrombospondin1 mimics rapidly relieve depression via Shank3 dependent uncoupling between dopamine D1 and D2 receptors.

Deficits in astrocyte function contribute to major depressive disorder (MDD) and suicide, but the therapeutic effect of directly reactivating astrocytes for depression remains unclear. Here, specific gains and losses of astrocytic cell functions in the medial prefrontal cortex (mPFC) bidirectionally regulate depression-like symptoms. Remarkably, recombinant human Thrombospondin-1 (rhTSP1), an astrocyte-secreted protein, exerted rapidly antidepressant-like actions through tyrosine hydroxylase (Th)/dopamine (DA)/dopamine D2 receptors (D2Rs) pathways, but not dopamine D1 receptors (D1Rs), which was dependent on SH3 and multiple ankyrin repeat domains 3 (Shank3) in the mPFC. TSP1 in the mPFC might have potential as a target for treating clinical depression.

Nonoxid-HMGB1 Attenuates Cognitive Impairment After Traumatic Brain Injury in Rats.

Traumatic brain injury (TBI) is a major global burden of health. As an accepted inflammatory mediator, high mobility group box 1 (HMGB1) is found to be effective in facilitating neurogenesis and axonal regeneration. SH3RF2 (also known as POSHER), an E3 ligase SH3 domain-containing ring finger 2, belongs to the SH3RF family of proteins. Here, we aimed to investigate the role of redox states of HMGB1 on neurite outgrowth and regeneration both in vitro and in vivo. In this study, distinct recombinant HMGB1 redox isoforms were used. Sequencing for RNA-seq and data analysis were performed to find the potential downstream target of nonoxid-HMGB1 (3S-HMGB1). Protein changes and distribution of SH3RF2 were evaluated by western blot assays and immunofluorescence. Lentivirus and adeno-associated virus were used to regulate the expression of genes. Nonoxid-HMGB1-enriched exosomes were constructed and used to treat TBI rats. Neurological function was evaluated by OF test and NOR test. Results demonstrated that nonoxid-HMGB1 and fr-HMGB1, but not ds-HMGB1, promoted neurite outgrowth and axon elongation. RNA-seq and western blot assay indicated a significant increase of SH3RF2 in neurons after treated with nonoxid-HMGB1 or fr-HMGB1. Notably, the beneficial effects of nonoxid-HMGB1 were attenuated by downregulation of SH3RF2. Furthermore, nonoxid-HMGB1 ameliorated cognitive impairment in rats post-TBI via SH3RF2. Altogether, our experimental results suggest that one of the promoting neurite outgrowth and regeneration mechanisms of nonoxid-HMGB1 is mediated through the upregulated expression of SH3RF2. Nonoxid-HMGB1 is an attractive therapeutic candidate for the treatment of TBI.

Targeting integrated stress response regulates microglial M1/M2 polarization and attenuates neuroinflammation following surgical brain injury in rat.

Integrated stress response (ISR) contributes to various neuropathological processes and acting as a therapy target in CNS injuries. However, the fundamental role of ISR in regulating microglial polarization remains largely unknown. Currently no proper pharmacological approaches to reverse microglia-driven neuroinflammation in surgical brain injury (SBI) have been reported. Here we found that inhibition of the crucial ISR effector, activating transcription factor 4 (ATF4), using the RNA interference suppressed the lipopolysaccharide (LPS)-stimulated microglial M1 polarization in vitro. Interestingly, counteracting ISR with a small-molecule ISR inhibitor (ISRIB) resulted in a significant microglial M1 towards M2 phenotype switching after LPS treatment. The potential underlying mechanisms may related to downregulate the intracellular NADPH oxidase 4 (NOX4) expression under the neuroinflammatory microenvironment. Notably, ISRIB ameliorated the infiltration of microglia and improved the neurobehavioral outcomes in the SBI rat model. Overall, our findings suggest that targeting ISR exerts a novel anti-inflammatory effect on microglia via regulating M1/M2 phenotype and may represent a potential therapeutic target to overcome neuroinflammation following SBI.

Surgical procedures including carotid-carotid crossover bypass and ring-stripping hybrid operation for Rile's type 1A common carotid artery occlusion: an experience of 6 cases.

BACKGROUND: At present, there is no consensus on the treatment of common carotid artery occlusion (CCAO). We explored the surgical indications and observed the therapeutic effects of carotid-carotid crossover bypass and ring-stripping hybrid operation for treatment of Rile's type 1A CCAO. METHODS: The imaging data, clinical manifestations, surgical complications and postoperative ischemic events were retrospectively collected from the 6 cases with Rile's type 1A CCAO that underwent surgery in our department from 2011 to 2018. Of the 6 cases, 4 received carotid-carotid crossover bypass and 2 ring-stripping hybrid operation. RESULTS: Of the 6 cases, 4 were male and 2 females, with a mean age of 62.7 years. All cases had the left CCAO combined with decreased computed tomography perfusion (CTP) in the left internal carotid artery blood supply area. In the 4 cases receiving carotid-carotid crossover bypass, the mean operation time was 186±13 min, the mean hospital stay was 17±1 d, postoperative CTP improved, one case had swallowing foreign body sensation, synthetic vascular grafts were patent and no ischemic events occurred during the mean follow-up of 62.3±26.3 months. In the 2 cases receiving ring-stripping hybrid operation, the mean operation time was 118±11 min, the mean hospital stay was 5.5±0.7 d, postoperative CTP improved, and the opened common carotid arteries (CCA) were patent and no ischemic events occurred during the mean follow-up of 17.5±3.5 months. CONCLUSIONS: Rile's type 1A CCAO with related symptoms and decreased CTP should be treated by revascularization. The carotid-carotid crossover bypass is a good choice in bypass schemes because of its easy operation and good long-term patency. The ring-stripping hybrid operation may be an ideal surgical scheme for Rile's type 1A CCAO.

Endoscopic anatomical study of the trans-lateral molar approach to the infratemporal fossa.

BACKGROUND: The infratemporal fossa (ITF) is located deep in the skull base. Recently, the endoscopic transoral approach has enabled maxillofacial surgeons to access the ITF using a less invasive approach compared to the traditional transfacial and endonasal endoscopic approaches. OBJECTIVE: The present study aims to provide maxillofacial surgeons with new data concerning direct endoscopic measurement and precise anatomical topography features of the endoscopic trans-lateral molar approach to ITF by comparing the endoscopic and regional anatomy of ITF. A clinical case receiving the proposed surgical approach is used to determine the feasibility of this technique. METHOD: The anatomical data were obtained by measuring the bone anatomical landmarks and analyzing the CT imaging data using GE's Advance Windows 4.1 software on 25 subjects (50 sides). Morphological pictures of the regional anatomy and endoscopic anatomy were obtained from 6 (12 sides) adult cadaver heads, and the anatomical features were described. The present study reports the management of one case using the proposed surgical approach. RESULTS: The proposed surgical approach clearly revealed neurovascular, muscular, and surgical landmarks in the ITF. The surgical case supports the minimally invasive treatment approach, which could rapidly access the ITF and completely excise benign tumors. CONCLUSION: The anatomical studies and surgical case presentation helps us understand the spatial relationship of surgical landmarks of the surgical approach to the ITF for the treatment of benign lesions in the deep cranial base area.

Suppression of CLC-3 chloride channel reduces the aggressiveness of glioma through inhibiting nuclear factor-κB pathway.

CLC-3 chloride channel plays important roles on cell volume regulation, proliferation and migration in normal and cancer cells. Recent growing evidence supports a critical role of CLC-3 in glioma metastasis, however, the mechanism underlying is unclear. This study finds that CLC-3 is upregulated in glioma tissues and positively correlated with WHO histological grade. Patients with high CLC-3 expression had an overall shorter survival time, whereas patients with low expression of CLC-3 had a better survival time. Silencing endogenous CLC-3 with ShCLC-3 adenovirus significantly decreases volume-regulated chloride currents, inhibits the nuclear translocation of p65 subunit of Nuclear Factor-κB (NF-κB), decreases transcriptional activity of NF-κB, reduces MMP-3 and MMP-9 expression and decreases glioma cell migration and invasion. Taken together, these results suggest CLC-3 promotes the aggressiveness of glioma at least in part through nuclear factor-κB pathway, and might be a novel prognostic biomarker and therapeutic target for glioma.

Glioma-derived ADAM10 induces regulatory B cells to suppress CD8+ T cells.

CD8+ T cells play an important role in the anti-tumor activities of the body. The dysfunction of CD8+ T cells in glioma is unclear. This study aims to elucidate the glioma cell-derived ADAM10 (A Disintegrin and metalloproteinase domain-containing protein 10) in the suppression of CD8+ effector T cells by the induction of regulatory B cells. In this study, glioma cells were isolated from surgically removed glioma tissue and stimulated by Phorbol myristate acetage (PMA) in the culture. The levels of ADAM10 in the culture were determined by enzyme-linked immunosorbent assay. Immune cells were assessed by flow cytometry. The results showed that the isolated glioma cells express ADAM10, which was markedly up regulated after stimulated with PMA. The glioma-derived ADAM10 induced activated B cells to differentiate into regulatory B cells, the later suppressed CD8+ T cell proliferation as well as the induced regulatory T cells, which also showed the immune suppressor effect on CD8+ effector T cell proliferation. In conclusion, glioma cells produce ADAM10 to induce Bregs; the latter suppresses CD8+ T cells and induces Tregs.

A new modified dura mater implant: characteristics in recipient dogs.

Duraplasty is critical to the maintenance of anatomical integrity and the protection of brain tissue. Allotransplantation of cadaveric dura mater was abandoned after it was found to transmit Creutzfeldt-Jakob disease (CJD). In this study, the usefulness of a xenogeneic dura mater for dural reconstruction was tested. Twelve dogs were randomly assigned to 4 groups. To simulate the condition of patients with brain surface injury, an area of approximately 2 cm x 1.5 cm of the dura mater was removed to create a defect. Xenogeneic dura mater derived from porcine pericardium was trimmed to the shape and size of the defect and sutured to the endogenous dura mater. Muscles at the apex of the skull and scalp were also sutured. Three dogs were euthanized at 3, 6, 9, and 12 months after implantation and the xenogeneic dura mater and surrounding endogenous tissue were examined macroscopically and microscopically. Three months after implantation, the graft site had begun to heal. Macroscopically, at 6, 9, and 12 months after implantation, the graft had healed completely with the surrounding tissue. No boundary between the graft and surrounding tissue was distinguishable, and the two could not be separated. The graft was smoothly epithelialized and nonadherent to the brain surface. Microscopically, the inner surface of the implant was covered with epithelial cells, and internal capillaries, subepithelial fibrous tissue deposition, and fibroblast proliferation were observed. The xenogeneic dura mater progressively degraded over time. No cysts and no neutrophilic or lymphocytic inflammatory cell response developed between the implant and the recipient brain parenchyma. The modified xenogeneic dura mater is sufficiently biocompatible to allow epithelialization of its inner surface without adherence to brain tissue. No abnormalities develop in recipients, and the xenograft is gradually biodegraded and replaced by endogenous tissue identical to the endogenous dura mater.

Correlation of MMP(1) and TIMP (1) expression with pituitary adenoma fibrosis.

OBJECTIVE: To explore the correlation of matrix metalloproteinase-1 (MMP(1)) and tissue inhibitor of metalloproteinase-1 (TIMP(1)) with pituitary adenoma fibrosis. METHODS: Thirty-eight pituitary adenoma specimens were divided into fibrous group (6 patients) and non-fibrous group (32 patients). MMP(1) and TIMP(1) expression was detected by RT-PCR and immunohistochemistry. The collagen content was determined by Sirius scarlet staining. RESULTS: In fibrous and non-fibrous group: (1) the collagen content was 20.95 +/- 8.42% and 7.98 +/- 5.18% respectively, and there was a statistical significance (P < 0.01). (2) The expression of MMP(1)mRNA was 0.47 +/- 0.40 and 0.59 +/- 0.54 respectively and its protein expression was 0.12 +/- 0.09 and 0.13 +/- 0.09 respectively, and there was no statistical significance (P > 0.05). Their expression was not related to collagen content (P > 0.05). (3) The expression of TIMP(1)mRNA was 1.61 +/- 1.09 and 0.79 +/- 0.59 respectively and its protein expression was 0.58 +/- 0.11 and 0.32 +/- 0.18 respectively, and there was a statistical significance (P < 0.01). Their expression was related to collagen content (P < 0.01). CONCLUSION: The pathological features of pituitary adenoma fibrosis are excessive collagen deposition. High expression of TIMP(1) may be an important cause.