The repair of the central nervous system (CNS) is a major challenge because of the difficulty for neurons or axons to regenerate after damages. Injectable hydrogels have been developed to deliver drugs or cells for neural repair, but these hydrogels usually require conditional stimuli or additional catalysts to control the gelling process. Self-healing hydrogels, which can be injected locally to fill tissue defects after stable gelation, are attractive candidates for CNS treatment. In the current study, the self-healing hydrogel with a semi-interpenetrating polymer network (SIPN) was prepared by incorporation of hyaluronan (HA) into the chitosan-based self-healing hydrogel. The addition of HA allowed the hydrogel to pass through a narrow needle much more easily. As the HA content increased, the hydrogel showed a more packed nanostructure and a more porous microstructure verified by coherent small-angle X-ray scattering and scanning electron microscopy. The unique structure of SIPN hydrogel enhanced the spreading, migration, proliferation, and differentiation of encapsulated neural stem cells in vitro. Compared to the pristine chitosan-based self-healing hydrogel, the SIPN hydrogel showed better biocompatibility, CNS injury repair, and functional recovery evaluated by the traumatic brain injury zebrafish model and intracerebral hemorrhage rat model. We proposed that the SIPN of HA and chitosan self-healing hydrogel allowed an adaptable environment for cell spreading and migration and had the potential as an injectable defect support for CNS repair.
Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults with a dismal prognosis. Current therapy of surgical removal combined with Temozolomide (TMZ) and radiation therapy only slightly prolongs the survival of GBM patients. Thus, it is essential to elucidate mechanism underlying its highly malignant properties in order to develop efficacious therapeutic regimens. In this study, we showed that progranulin (PGRN) was overexpressed in most GBM cell lines and the majority of human tumor samples. PGRN overexpression conferred GBM cells with tumorigenic properties and TMZ resistance by upregulating DNA repair (PARP, ATM, BRCA1, Rad51, XRCC1 and so on) and cancer stemness (CD133, CD44, ABCG2) genes, in part via an AP-1 transcription factor, specifically cFos/JunB. Curcumin, an AP-1 inhibitor, was also found to regulate PGRN promoter activity and expression including its downstream effectors aforementioned. These data suggested a feedforward loop between PGRN signaling and AP-1. PGRN depletion significantly decreased unlimited self-renewal and multilineage differentiation and the malignant properties of GBMs cells S1R1, and enhanced their vulnerability to TMZ. In addition, S1R1 depleted of PGRN also lost the ability to form tumor in an orthotopic xenograft mouse model. In conclusion, PGRN had a critical role in the pathogenesis and chemoresistance of GBM and functioned at the top of the hierarchy of cellular machinery that modulates both DNA repair pathways and cancer stemness. Our data suggest that a new strategy combining current regimens with compounds targeting PGRN/AP-1 loop like curcumin may significantly improve the therapeutic outcome of GBM.
Despite extensive efforts in recent years, the blood-brain barrier (BBB) remains a significant obstacle for drug delivery. This study proposes using a clinical extracorporeal shockwave instrument to open the BBB, combined with a laser assisted bi-axial locating platform to achieve non-invasive, controllable-focus and reversible BBB opening in the brains of rats. Under shockwave treatment with an intensity level of 5 (P–9.79 MPa, energy flux density (EFD) 0.21 mJ/mm2) and a pulse repetition frequency of 5 Hz, the BBB could be opened after 50 shocks without the use of an ultrasound contrast agent. With the proposed method, the BBB opening can be precisely controlled in terms of depth, size and location. Moreover, a shockwave based gene transfection was demonstrated using a luciferase gene.
Early parenchymal CE is associated with hemorrhage progression, cerebral edema, clinical deterioration, and need for subsequent surgery. These patients should be monitored closely, and early surgery may be needed if deterioration occurs. Further elucidation of the pathophysiology is needed to formulate effective treatment for these high-risk patients.
Objective: It has been noted that the posterior circulation serves as an important source of collateral blood supply in moyamoya disease. Since most of the literature has focused on non-operative cases and many symptomatic patients receive surgical revascularization, we evaluated the posterior circulation changes after revascularization and found that progressive posterior cerebral artery (PCA) steno-occlusive changes after revascularization caused cerebral hemodynamic compromise and clinical deterioration in a significant portion of patients. Methods: Twenty-three moyamoya disease patients with ischemic presentation who received revascularization with complete angiography and xenon CT during a minimum of 3 years’ clinical follow-up were enrolled. Revascularization was performed in 38 hemispheres. Pre- and postoperative angiography were reviewed to determine the internal carotid artery (ICA) stage, PCA stage, leptomeningeal collateral (LMC) grade, and Matsushima synangiosis grade. The postoperative regional cerebral blood flow (CBF) and cerebral vascular reserve (CVR) were recorded and correlated with angiographic findings and clinical outcome. Results: Progression of ICA staging was noted in 23 sides (55.2%), and progression of PCA staging was noted in 18 sides (47.4%). Among the 18 cases of PCA stage progression, an associated decrease in LMC grade was noted in 12 sides (66.7%). These changes were associated with decreased regional CBF and CVR, which also explained the recurrent ischemic symptoms in 27.8% of these patients. In contrast, LMC grade increased in 15 (65.2%) sides of patients with ICA progression. Conclusions: Progressive steno-occlusive change in the PCA after revascularization is associated with a reduction in LMC blood flow and cerebral ischemia in moyamoya patients. This phenomenon might cause recurrent ischemic symptoms in 27.8% of patients.
Hydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage (aSAH) and reportedly contributes to poor neurological outcomes. In this review, we summarize the molecular and cellular mechanisms involved in the pathogenesis of hydrocephalus following aSAH and summarize its treatment strategies. Various mechanisms have been implicated for the development of chronic hydrocephalus following aSAH, including alterations in cerebral spinal fluid (CSF) dynamics, obstruction of the arachnoid granulations by blood products, and adhesions within the ventricular system. Regarding molecular mechanisms that cause chronic hydrocephalus following aSAH, we carried out an extensive review of animal studies and clinical trials about the transforming growth factor-β/SMAD signaling pathway, upregulation of tenascin-C, inflammation-dependent hypersecretion of CSF, systemic inflammatory response syndrome, and immune dysregulation. To identify the ideal treatment strategy, we discuss the predictive factors of shunt-dependent hydrocephalus between surgical clipping and endovascular coiling groups. The efficacy and safety of other surgical interventions including the endoscopic removal of an intraventricular hemorrhage, placement of an external ventricular drain, the use of intraventricular or cisternal fibrinolysis, and an endoscopic third ventriculostomy on shunt dependency following aSAH were also assessed. However, the optimal treatment is still controversial, and it necessitates further investigations. A better understanding of the pathogenesis of acute and chronic hydrocephalus following aSAH would facilitate the development of treatments and improve the outcome.
Although surgical excision of meningioma and its dural base is the most common primary management, skull base meningiomas are quite different, and contemporary management usually consists of multimodal treatment with the aim of achieving the best possible functional outcome and quality of life (QOL) for these patients. As surgery plays an important role in the treatment of skull base meningiomas, it is crucial for neurosurgeons to appreciate the surgical outcome and QOL after meningioma surgery. Outcome is usually measured for meningiomas in terms of morbidity, mortality, time to recurrence, and QOL. The extent of resection, tumor grade, proliferative markers, and tumor location are significant factors in predicting the surgical outcome. Therefore, we address each of these factors in detail in this review. Advances in recent decades in microsurgical techniques, neuroimaging modalities, neuroanesthesia, and perioperative intensive care have substantially improved the surgical outcome; therefore, most surgical outcomes discussed in this review are cited from contemporary literature (2000 to the present) in order to depict the surgical outcome of contemporary microsurgery.
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