VCAM-1-binding peptide targeted cationic liposomes containing NLRP3 siRNA to modulate LDL transcytosis as a novel therapy for experimental atherosclerosis.

BACKGROUND: Activation of NLRP3 inflammasome accelerates the formation of atherosclerotic plaques. Here, we evaluated the effects of inflammation on the expression of the NLRP3 inflammasome in endothelial cells (ECs). METHODS: The effect of TNF-α on transcytosis of LDL was measured. VCAM-1 binding peptide targeting cationic liposomes (PCLs) were prepared as siRNA vectors. Methylated NLRP3 siRNA was encapsulated into the PCLs to knock down NLRP3 in vitro and in vivo. In rats with partial carotid ligation, TNF-α-induced LDL retention in the carotid artery endothelium was observed. In ApoE-/- mice, NLRP3 siRNA-PCLs were injected intravenously to observe their effect on the formation of atherosclerosis. RESULTS: Our results showed that TNF-α upregulated NLRP3 in ECs, promoting the assembly of the NLRP3 inflammasome and processing of pro-IL-1ß into IL-1ß. Moreover, TNF-α accelerated LDL transcytosis in ECs. Knockdown of NLRP3 prevented TNF-α-induced NLPR3 inflammasome/IL-1ß signaling and LDL transcytosis. Using optimized cationic liposomes to encapsulate methylated NLRP3 siRNA, resulting in targeting of VCAM-1-expressing ECs, to knockdown NLRP3, TNF-α-induced NLRP3 inflammasome activation and LDL transcytosis were prevented. Using the partial carotid ligation as an atherosclerosis rat model, we found that local administration of NLRP3 siRNA-PCLs efficiently knocked down NLPR3 expression in the carotid endothelium and dramatically attenuated the deposition of atherogenic LDL in carotid ECs in TNF-α-challenged rats. Furthermore, NLRP3 siRNA-PCLs were injected intravenously in ApoE-/- mice, resulting in reduced plaque formation. CONCLUSION: These findings established a novel strategy for targeting the NLRP3 inflammasome using NLRP3 siRNA-PCLs to interrupt LDL transcytosis, representing a potential novel therapy for atherosclerosis.

Multicentric Glioma: An Ideal Model to Reveal the Mechanism of Glioma.

As a special type of glioma, multicentric glioma provides an ideal pathological model for glioma research. According to the stem-cell-origin theory, multiple lesions of multicentric glioma share the same neuro-oncological origin, both in gene level and in cell level. Although the number of studies focusing on genetic evolution in gliomas with the model of multicentric gliomas were limited, some mutations, including IDH1 mutations, TERTp mutations and PTEN deletions, are found to be at an early stage in the process of genetic aberrance during glioma evolution based on the results of these studies. This article reviews the clinical reports and genetic studies of multicentric glioma, and intends to explain the various clinical phenomena of multicentric glioma from the perspective of genetic aberrance accumulation and tumor cell evolution. The malignant degree of a glioma is determined by both the tumorigenicity of early mutant genes, and the stemness of early suffered cells.

A Non-Isocyanate Route to Poly(Ether Urethane): Synthesis and Effect of Chemical Structures of Hard Segment.

A series of non-isocyanate poly(ether urethane) (PEU) were prepared by an environmentally friendly route based on dimethyl carbonate, diols and a polyether. The effect of the chemical structure of polyurethane hard segments on the properties of this kind of PEU was systematically investigated in this work. Polyurethane hard segments with different structures were first prepared from hexamethylene di-carbamate (BHC) and different diols (butanediol, hexanediol, octanediol and decanediol). Subsequently, a series of non-isocyanate PEU were obtained by polycondensation of the polyurethane hard segments with the polyether soft segments (PTMG2000). The PEU were characterized by GPC, FT-IR, 1H NMR, DSC, WAXD, SAXS, AFM and tensile testing. The results show that the urea groups generated by the side reaction affect the degree of crystallization of hard segments by influencing the hydrogen bonding of the hard segments molecular chains. The degree of hard segment crystallization, in turn, affects the thermal and mechanical properties of the polymer. The urea group content is related to the carbon chain length of the diol used for the synthesis of hard segments. When butanediol is applied to synthesize hard segment, the hard segment of the resulting PEU is unable to crystallize. Therefore, the tensile strength and modulus of elasticity of butanediol-based PEU is lowest among three, though it possesses the highest urea group content. When longer octanediol or decanediol is applied to synthesize the hard segment, the hard segments in the resulting polyether-based polyurethane are crystallizable and the resulting PEU possesses higher tensile strength.

microRNA-455-5p alleviates neuroinflammation in cerebral ischemia/reperfusion injury.

Neuroinflammation is a major pathophysiological factor that results in the development of brain injury after cerebral ischemia/reperfusion. Downregulation of microRNA (miR)-455-5p after ischemic stroke has been considered a potential biomarker and therapeutic target for neuronal injury after ischemia. However, the role of miR-455-5p in the post-ischemia/reperfusion inflammatory response and the underlying mechanism have not been evaluated. In this study, mouse models of cerebral ischemia/reperfusion injury were established by transient occlusion of the middle cerebral artery for 1 hour followed by reperfusion. Agomir-455-5p, antagomir-455-5p, and their negative controls were injected intracerebroventricularly 2 hours before or 0 and 1 hour after middle cerebral artery occlusion (MCAO). The results showed that cerebral ischemia/reperfusion decreased miR-455-5p expression in the brain tissue and the peripheral blood. Agomir-455-5p pretreatment increased miR-455-5p expression in the brain tissue, reduced the cerebral infarct volume, and improved neurological function. Furthermore, primary cultured microglia were exposed to oxygen-glucose deprivation for 3 hours followed by 21 hours of reoxygenation to mimic cerebral ischemia/reperfusion. miR-455-5p reduced C-C chemokine receptor type 5 mRNA and protein levels, inhibited microglia activation, and reduced the production of the inflammatory factors tumor necrosis factor-α and interleukin-1ß. These results suggest that miR-455-5p is a potential biomarker and therapeutic target for the treatment of cerebral ischemia/reperfusion injury and that it alleviates cerebral ischemia/reperfusion injury by inhibiting C-C chemokine receptor type 5 expression and reducing the neuroinflammatory response.

Exposure region of the Kawase approach and its correlation with skull base anatomy: An evaluation with digital models.

The Kawase approach is one of the most used trajectories in skull base surgery. The exposure range of the approach and its correlation with skull base anatomy still demand more exploration. With the help of digital rebuilding, analysis, and measurement, we evaluated the exposure range of the Kawase and extended Kawase approaches and analyzed the correlation between the exposure range and the variants of the petrosal and clival anatomy. The finding of the study demonstrated that compared to the sub-temporal approach, the Kawase approach and the extended Kawase approach significantly added the exposure range in the upper, middle, and partial inferior regions of the clivus. The gains in the exposure volume and area are more when the manipulation angle is less than 135°.

Preferential Targeting Cerebral Ischemic Lesions with Cancer Cell-Inspired Nanovehicle for Ischemic Stroke Treatment.

The poor drug delivery to cerebral ischemic regions is a key challenge of ischemic stroke treatment. Inspired by the intriguing blood-brain barrier (BBB)-penetrating ability of 4T1 cancer cells upon their brain metastasis, we herein designed a promising biomimetic nanoplatform by camouflaging a succinobucol-loaded pH-sensitive polymeric nanovehicle with a 4T1 cell membrane (MPP/SCB), aiming to promote the preferential targeting of cerebral ischemic lesions to attenuate the ischemia/reperfusion injury. In transient middle cerebral artery occlusion (tMCAO) rat models, MPP/SCB could be preferentially delivered to the ischemic hemisphere with a 4.79-fold higher than that in the normal hemisphere. Moreover, MPP/SCB produced notable enhancement of microvascular reperfusion in the ischemic hemisphere, resulting in a 69.9% reduction of infarct volume and showing remarkable neuroprotective effects of tMCAO rats, which was superior to the counterpart uncamouflaged nanovehicles (PP/SCB). Therefore, this design provides a promising nanoplatform to target the cerebral ischemic lesions for ischemic stroke therapy.

Potential of Exosomes for the Treatment of Stroke.

Stroke is the result of blockage or rupture of blood vessels in the brain and is the leading cause of death and disability in the world. Currently only a very limited number of therapeutic approaches are available for treatment of stroke patients, and the vast majority of neuroprotective agents that tested positively in pre-clinical studies failed in clinical trials. In recent years, the clinical value of the use of exosomes for stroke treatment has received widespread attention due their unique characteristics such as low immunogenicity, low toxicity and biodegradability, ability to cross the blood-brain barrier (BBB), and their important role in communication between cells. More and more evidence suggests that the secretion of exosomes is the mechanism underlying the protection induced by mesenchymal stromal cells (MSCs) after stroke. Exosomes are thought to support brain restoration and induce repairing effects, including neurovascular remodeling, and anti-apoptosis and anti-inflammatory effects. Recent reports have focused on the clinical application of exosomes as a potential drug delivery approach. This review focuses on the ability of exosomes to interrupt the stroke-induced pathologic processes of stroke, and on publications describing how to achieve more effective treatment of stroke with exosomes.

Combination of dura turning-over and decompressive craniectomy: a new pattern of surgery for cerebral infarction caused by craniocerebral gunshot injury.

BACKGROUND: Craniocerebral gunshot injury refers to a wound caused by a bullet passing through or lodged in brain tissue, resulting in the loss of function of a certain area or other fatal damage to the human brain. Craniocerebral gunshot injury is usually life-threatening and is very common in modern warfare, accounting for the majority of battle casualties. Most of the patients suffer from acute cerebral infarction caused by vascular injury. Lack of early and solid battlefield emergency medical interference adds to the risk of death among the wounded. CASE PRESENTATION: We present a 24-year-old man who was shot with a shotgun from a distance of 15 m in an accidental injury. Forty-seven grapeshots were found on his body surface by physical examination. A computed tomography (CT) scan demonstrated large areas of low-density shadows in his right parietal lobe and right temporal lobe with the midline shifting to the left side 2 days later. Afterwards, the patient was transferred to our emergency medical center at Changzheng Hospital in Shanghai. Cranial computed tomography angiography (CTA) showed a high-density shadow in the initial part of the right middle cerebral artery. The branches after the initial part were obliterated. Prompt medical attention and decompressive craniotomy (DC) surgery contributed to the final recovery from cerebral infarction of this patient. CONCLUSION: Bullets can penetrate or be lodged in the brain, causing intracranial hypertension. The bullets lodged in the brain can result in stenosis and embolism of a cerebral artery, causing acute cerebral infarction. Combining dura turning-over surgery with DC surgery can not only decrease intracranial pressure, which can increase the blood supply for hypertension-induced vessel stenosis, but also help vessels outside the dura mater grow into ischemic areas of the cerebral cortex. However, this new pattern of surgery needs further support from evidence-based medicine.

Surgical treatment achieves better outcome in severe traumatic pericallosal aneurysm: case report and literature review.

Traumatic pericallosal aneurysm (TPA) is typically seldom yet potentially lethal. Because of its rarity, also complicated by the unpredictable delayed-onset, TPA is more difficult to be diagnosed promptly. Due to the sporadic reports and diverse opinions on the priority of surgical treatment, a consensus about effective management of TPA has not been reached. Here we report a 55 year-old male patient with TPA, who received an emergent craniotomy to clip the pseudoaneurysm and remove the hematoma under intense intracranial pressure (ICP) monitoring. A satisfactory clinical outcome was achieved at a 3-month follow-up. Thereafter, a review was conducted to evaluate the outcomes of different managing modalities.

LncRNA and mRNA interaction study based on transcriptome profiles reveals potential core genes in the pathogenesis of human glioblastoma multiforme.

OBJECTIVES: To study the expression profiles of lncRNA and mRNA in glioblastoma multiforme (GBM) and to find potential core genes in the pathogenesis of this high malignant disease. METHODS: Agilent Microarray (Arrystar v2.0) was used to detect the expressions of 33,045 lncRNAs and 30,215 coding transcripts in 5 GBM and 5 normal brain samples. Differentially expressed lncRNAs and mRNAs were identified through Volcano Plot filtering. The expressions of six lncRNAs were further detected by qPCR to validate the results of microarray. The function of differential mRNA was determined by pathway and GO analysis, and the function of lncRNAs was studied by subgroup analysis and by their physical or functional relationships with corresponding mRNAs. RESULTS: A total of 815 lncRNAs and 738 mRNAs are found to be differentially expressed between the GBM and normal brain groups. With the expression of these differentially expressed genes, the two group samples could be clearly differentiated. The result of qPCR has showed a good consistency with the microarray, thus proving the accuracy of the microarray data. GO and Pathway analyses have proved that the functions of differentially expressed mRNAs in GBM related closely with many processes that important in the cancer pathogenesis. Core lncRNAs and mRNAs that may play important roles in the pathogenesis of GBM are revealed and listed according to various methods. CONCLUSION: The GBM shows an aberrant expression profile of lncRNA and mRNA. Potential core genes are revealed by the lncRNA and mRNA interaction study based on transcriptome profiles in GBM.

Microvascular decompression surgery is effective for the laterocollis subtype of spasmodic torticollis: a long-term follow-up result.

BACKGROUND: Spasmodic torticollis (ST) is characterized by sustained, involuntary, and painful spasms of specific muscle (s), which results into abnormal posture of the neck and head. Although various treatments for ST have been introduced, none of them shows absolute effectiveness. Earlier research from our department showed that microvascular decompression (MVD) surgery is effective in the short-term for ST patients with confirmed accessory nerve compression. However, the long-term outcome of MVD remains unknown. METHOD: Twelve ST patients with confirmed accessory nerve compression received MVD surgery of their accessory nerves. We utilized the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) to evaluate the long-term outcome (5.4 ± 0.87 years). RESULTS: The MVD lowered total TWSTRS scores by 42.8 % in all ST patients. This result, however, only counted for moderate relief. Interestingly, we observed that the laterocollis (LC) subtypes of ST (n = 3) obtained a higher TWSTRS score improvement (86.9 ± 6.2 %), compared to that of the non-LC (28.1 ± 12 %) (P =0.0001). Additionally, the disability (92.7 ± 2 %) subscale score in the LC subtypes had the most prominent improvement compared to the pain (88.1 ± 5.1 %) and severity (81.3 ± 10.5 %). CONCLUSIONS: In the cases of confirmed accessory nerve compression, the MVD could be considered as a treatment alternative for ST, especially for the LC subtypes.

Which is the best peri-operative anti-coagulative therapy of transverse sinus stenting for refractory idiopathic intracranial hypertension?

Treatment of refractory idiopathic intracranial hypertension (IIH) is a challenging problem. We reported a refractory IIH patient who manifested with typical intracranial hypertensive symptoms successfully treated with endovascular stent implantation. Pre-operative cerebrospinal fluid (CSF) opening pressure is 36 cmH2O. Cerebral angiography demonstrated a stenotic lesion located at the right transverse sinus (TS). The stenotic TS returned to its normal caliber and the pressure gradient deceased from 36 mmHg to 4 mmHg after the stent placement. The intracranial hypertensive symptoms resolved and one month later, the CSF opening pressure decreased to 14 cmH2O.

Microvascular decompression of the accessory nerve for treatment of spasmodic torticollis: early results in 12 cases.

PURPOSE: To describe the early effectiveness of microvascular decompression (MVD) for the treatment of spasmodic torticollis (ST). METHODS: Twelve patients with spasmodic torticollis were treated by microvascular decompression of the accessory nerves using a microscopic neurosurgical technique via the retrosigmoid approach. The most common compressing blood vessels were the ipsilateral posterior inferior cerebral artery (PICA) and/or the vertebral artery. The intraoperative monitor was introduced to detect the accessory nerve and to avoid unnecessary damage to the nerve. RESULTS: Ten patients were cured (83%), and the other two (17%) improved with moderate spasms. In most cases, the improvement was noticed 1 week after the operation. No operation-related complications were observed during the follow-up period, which ranged from 2 months to 3 years. CONCLUSIONS: The early effect of MVD for some patients with spasmodic torticollis was satisfactory, but the long-term results need to be assessed further.