Deposition of Gadolinium in the Central and Peripheral Nervous Systems and Its Effects on Sensory, Cognitive, and Athletic Implications after Multiple Injections of Gadolinium-Based Contrast Agents in Rats.

BACKGROUND AND PURPOSE: After repeat administration of gadolinium-based contrast agents (GBCAs), the association between gadolinium retention in the central and peripheral nervous systems and the main manifestations of myelopathy and progressive neurologic symptoms remains unclear. We investigated the effects of the repeat administration of GBCAs on gadolinium retention in the central and peripheral nervous systems and the sensory, cognitive, and athletic implications. MATERIALS AND METHODS: Forty-eight male Wistar rats (6 weeks of age) were randomly divided into 4 experimental groups (12 rats in each group): the gadodiamide group (linear and nonionic GBCAs), the gadopentetate dimeglumine group (linear and ionic GBCAs), the gadoterate meglumine group (macrocyclic and ionic GBCAs), and the control group (0.9% saline solution). The brains of the rats were scanned using 9.4T MRI. Sensory behavioral tests were performed to assess the effect of GBCAs on pain sensitivity function. Gadolinium deposition in the brain, spinal cord, and peripheral nerves was determined by inductively coupled plasma mass-spectrometry. Transmission electron microscopy was used to observe the microscopic distribution of gadolinium after deposition in the spinal cord. The histopathologic features in the spinal cord were analyzed by H&E staining, Nissl staining, glial fibrillary acidic protein staining, and neuron-specific enolase staining after administration of GBCAs. RESULTS: All GBCAs resulted in gadolinium deposition in the central and peripheral nerve tissues, with the highest deposition in the sciatic nerve tissue (mean, 62.86 [SD, 12.56] nmol/g). Decreased muscle power, impairment of spatial cognitive function power, and pain hypersensitivity to thermal and mechanical stimuli were observed after exposure to gadodiamide. At the spinal cord, transmission electron microscopy found that the region of gadolinium depositions had a spheric structure similar to "sea urchins" and was mainly located near the vascular basement membrane. CONCLUSIONS: Multiple injections of GBCAs caused gadolinium deposition in the brain, spinal cord, and peripheral nerves, especially in the spinal cords of the gadodiamide group. Gadodiamide led to pain hypersensitivity and decreased muscle power and cognitive ability. For the patients who are hypersensitive to pain and need multiple MRI examinations, we recommend using macrocyclic GBCAs and the lowest dose possible.

Effects of Gadolinium Retention in the Brains of Type 2 Diabetic Rats after Repeated Administration of Gadolinium-Based MRI Contrast Agents on Neurobiology and NLRP3 Inflammasome Activation.

BACKGROUND: The neurotoxic potential of gadolinium (Gd)-based contrast agents (GBCAs) retention in the brains of patients with type 2 diabetes mellitus (T2DM) is unclear. PURPOSE: To determine the deposition and clearance of GBCAs in T2DM rats and the mechanism by which Gd enhances nucleotide-binding oligomerization domain-3 (NLRP3) inflammasome activation. STUDY TYPE: Cross-sectional, prospective. ANIMAL MODEL: 104 T2DM male Wistar rats. FIELD STRENGTH/SEQUENCE: 9.4-T, T1-weighted fast spin echo sequence. ASSESSMENT: T2DM (male Wistar rats, n = 52) and control group (healthy, male Wistar rats, n = 52) rats received saline, gadodiamide, Gd-diethylenetriaminepentaacetic acid, and gadoterate meglumine for four consecutive days per week for 7 weeks. The distribution and clearance of Gd in the certain brain were assessed by MRI (T1 signal intensity and relaxation rate R1, on the last day of each week), inductively coupled plasma mass-spectroscopy, ultraperformance liquid chromatography mass spectrometry, and transmission electron microscopy. Behavioral tests, histopathological features, and the effects of GBCAs on neuroinflammation were also analyzed. STATISTICAL TESTS: One-way analysis of variance, bonferroni method, and unpaired t-test. A P-value <0.05 was considered statistically significant. RESULTS: The movement distance and appearance time in the open field test of the T2DM rats in the gadodiamide group were significantly shorter than in the other groups. Furthermore, the expression of NLRP3, Pro-Caspase-1, interleukin-1ß (IL-1ß), and apoptosis-associated speck-like protein containing a CARD protein in neurons was significantly higher in the gadodiamide group than in the saline group, as shown by Western blot. Gadodiamide also induced differentiation of microglia into M1 type, decreased the neuronal mitochondrial membrane potential, and significantly increased neuronal apoptosis from flow cytometry. DATA CONCLUSION: T2DM may affect both the deposition and clearance of GBCAs in the brain. Informed by the T2DM model, gadodiamide could mediate the neuroinflammatory response by NLRP3 inflammasome activation. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.

Supplementation of hyaluronic acid injections with vitamin D improve knee function by attenuating synovial fluid oxidative stress in osteoarthritis patients with vitamin D insufficiency.

Objectives: There is still controversy about the effect of vitamin D supplementation on osteoarthritis (OA). The purpose of this study was to investigate the effects of vitamin D supplementation with Hyaluronic acid (HA) injection on OA. Methods: We investigated serum vitamin D levels and oxidative stress (OS) in synovial fluid from patients with OA who underwent total knee arthroplasty (grade IV, n = 24) and HA injection (grade II and III, n = 40). The effects of HA injection with or without oral vitamin D supplementation on synovial fluid OS and knee pain and function were then further investigated. Finally, patients underwent HA injection were divided into two groups according to vitamin D levels (vitamin D < or > 30 ng/ml), and the efficacy of the two groups were compared. Results: The results showed that the levels of glutathione peroxidase (GSH-PX) (P < 0.05) in the synovial fluid were lower in patients with stage IV OA than that in patients with stage II-III OA, while the levels of malondialdehyde (MDA) (P < 0.05) and lactate dehydrogenase (LDH) (P < 0.01) were significantly higher. Moreover, we found that age, BMI and vitamin D levels were significantly associated with the levels of oxidants and/or antioxidants in synovial fluid, and that vitamin D was significantly negatively correlated with BMI (R = -0.3527, p = 0.0043). Supplementation of HA injections with vitamin D significantly reduced the OS status in synovial fluid, attenuated knee pain and improved knee function in OA patients with vitamin D insufficiency. Conclusion: We conclude that maintenance of vitamin D sufficiency may be beneficial for the treatment of OA by improving OS in synovial fluid.

Ubiquitin-specific peptidases: Players in bone metabolism.

Osteoporosis is an ageing-related disease, that has become a major public health problem and its pathogenesis has not yet been fully elucidated. Substantial evidence suggests a strong link between overall age-related disease progression and epigenetic modifications throughout the life cycle. As an important epigenetic modification, ubiquitination is extensively involved in various physiological processes, and its role in bone metabolism has attracted increasing attention. Ubiquitination can be reversed by deubiquitinases, which counteract protein ubiquitination degradation. As the largest and most structurally diverse cysteinase family of deubiquitinating enzymes, ubiquitin-specific proteases (USPs), comprising the largest and most structurally diverse cysteine kinase family of deubiquitinating enzymes, have been found to be important players in maintaining the balance between bone formation and resorption. The aim of this review is to explore recent findings highlighting the regulatory functions of USPs in bone metabolism and provide insight into the molecular mechanisms governing their actions during bone loss. An in-deep understanding of USPs-mediated regulation of bone formation and bone resorption will provide a scientific rationale for the discovery and development of novel USP-targeted therapeutic strategies for osteoporosis.

Generation of neural organoids for spinal-cord regeneration via the direct reprogramming of human astrocytes.

Organoids with region-specific architecture could facilitate the repair of injuries of the central nervous system. Here we show that human astrocytes can be directly reprogrammed into early neuroectodermal cells via the overexpression of OCT4, the suppression of p53 and the provision of the small molecules CHIR99021, SB431542, RepSox and Y27632. We also report that the activation of signalling mediated by fibroblast growth factor, sonic hedgehog and bone morphogenetic protein 4 in the reprogrammed cells induces them to form spinal-cord organoids with functional neurons specific to the dorsal and ventral domains. In mice with complete spinal-cord injury, organoids transplanted into the lesion differentiated into spinal-cord neurons, which migrated and formed synapses with host neurons. The direct reprogramming of human astrocytes into neurons may pave the way for in vivo neural organogenesis from endogenous astrocytes for the repair of injuries to the central nervous system.

Cancer nanomedicine toward clinical translation: Obstacles, opportunities, and future prospects.

With the integration of nanotechnology into the medical field at large, great strides have been made in the development of nanomedicines for tackling different diseases, including cancers. To date, various cancer nanomedicines have demonstrated success in preclinical studies, improving therapeutic outcomes, prolonging survival, and/or decreasing side effects. However, the translation from bench to bedside remains challenging. While a number of nanomedicines have entered clinical trials, only a few have been approved for clinical applications. In this review, we highlight the most recent progress in cancer nanomedicine, discuss current clinical advances and challenges for the translation of cancer nanomedicines, and provide our viewpoints on accelerating clinical translation. We expect this review to benefit the future development of cancer nanotherapeutics specifically from the clinical perspective.

Endoscopic surgery versus craniotomy in the treatment of spontaneous intracerebral hematoma: a systematic review and meta-analysis.

BACKGROUND: Spontaneous intracerebral hemorrhage (SICH) has high morbidity and mortality, with no clear standard of treatment available. Compared with the craniotomy approach, neuroendoscopy is a relatively minimally invasive treatment method, and may be an efficient alternative. Therefore, this meta-analysis aimed to assess the clinical efficacy of neuroendoscopy and craniotomy in SICH patients. METHODS: The electronic databases Web of Science, PubMed, EmBase, MEDLINE, and the Cochrane Library were systematically searched. According to the PRISMA template, we finally selected and analyzed 14 eligible studies that evaluated neuroendoscopy versus craniotomy. Primary outcomes included operation time, intraoperative blood loss volume, evacuation rate, residual hematoma, complications, hospital stay duration, clinical outcomes, and other parameters. RESULTS: A total of 4 randomized controlled trials (RCTs) and 10 retrospective studies (non-RCTs) involving 1652 patients were included in the final analysis. In the neuroendoscopy (NE) group, operation time (p < 0.00001), intraoperative blood loss volume (p < 0.0001), hematoma evacuation rate (p = 0.0002), complications (p < 0.00001), hospitalization days (p = 0.004), and mortality (p < 0.0001) were significantly different from those of the craniotomy (C) group, with a higher rate of good recovery compared with the craniotomy group (P < 0.00001). CONCLUSIONS: These findings suggest that patients with SICH and physicians may benefit more from neuroendoscopic surgery than craniotomy.

Nanosonosensitizer-Augmented Sonodynamic Therapy Combined with Checkpoint Blockade for Cancer Immunotherapy.

INTRODUCTION: Sonodynamic therapy (SDT) has good targeting and non-invasive advantages in the treatment of solid cancers, and checkpoint blockade immunotherapy is also a promising treatment to cure cancer. However, their antitumor effects are not sufficient due to some inherent factors. Some studies that combined SDT with immunotherapy or nanoparticles have managed to enhance its efficiency to treat cancers. METHODS: In this work, an effective therapeutic strategy that can potentiate the antitumor efficacy of anti-PD-L1 antibody (aPD-L1) is developed by the use of cascade immuno-sonodynamic therapy (immuno-SDT). Titanium dioxide (TiO2), a nanostructured agent for SDT, sonosensitizer Chlorin e6 (Ce6), and immunological adjuvant CpG oligonucleotide (CpG ODN), are used to construct a multifunctional nanosonosensitizer (TiO2-Ce6-CpG). Then, we conducted in vitro and in vivo experiments to explore the antitumor effect of TiO2-Ce6-CpG under ultrasound (US) treatment. RESULTS: The characterization tests showed that the nanosonosensitizers are polycrystalline structure with homogeneous sizes, resulting in a good drug loading efficiency. The innovative nanosonosensitizers (TiO2-Ce6-CpG) can not only effectively inhibit tumor growth but also stimulate the immune system to activate the adaptive immune responses, using the TiO2-Ce6 to augment SDT and the immune adjuvant CpG to enhance the immune response. After combined with the aPD-L1, the synergistic effect could not only efficiently inhibit the primary tumor growth but also lead to an inhibition of the non-irradiated pre-existing distant tumors by inducing a strong tumor-specific immune response. CONCLUSION: In this study, we present an effective strategy for tumor treatment by combining nanosonosensitizer-augmented SDT and aPD-L1 checkpoint blockade. This work provides a promising strategy and offers a new vision for treating malignant tumors.

RING-finger protein 5 promotes hepatocellular carcinoma progression and predicts poor prognosis.

Hepatocellular carcinoma (HCC) is one of the most common cause of malignancy-related deaths. Recently, RING-finger protein 5 (RNF5), an E3 ubiquitin ligase, was revealed to be associated with the development of several human cancers. However, the clinical implication and functional role of RNF5 in HCC are poorly understood. We analysed RNF5 expression in HCC samples and observed that both the mRNA and protein levels of RNF5 were significantly increased in HCC tissues. RNF5 upregulation was markedly associated with larger tumour size, more satellite foci, and higher alpha fetoprotein (AFP) level, indicating poor prognosis in patients with HCC. Knockdown and overexpression experiments demonstrated that RNF5 promoted the proliferation, migration, and invasion of HCC cells in vitro. Moreover, RNF5 facilitated HCC growth in vivo. Our findings indicated that RNF5 was an oncogene of HCC progression and could be used as a novel prognostic biomarker and therapeutic target for patients with HCC.

Failure of enhanced recovery programs after laparoscopic radical gastrectomy: a single-center retrospective study.

BACKGROUND: Enhanced recovery programs (ERPs), as a rapid rehabilitation method, have been widely used in gastric cancer patients. Although many related studies have confirmed their effectiveness, some patients may still experience poor clinical outcomes. This study analyzed risk factors associated with ERP failure after laparoscopic radical gastrectomy. METHODS: We analyzed the outcomes of 212 patients who underwent ERP following laparoscopic radical gastrectomy between March 2017 and December 2019. The ERP included preoperative education, short periods of fasting, non-mechanical intestinal preparation, early ambulation and oral feeding. ERP failure was defined as more than 7 days of hospitalization due to postoperative complications, unplanned readmission within 30 days of surgery, or death. RESULTS: The mean patient age was 62 years (range 39-89 years). Surgical procedures included total gastrectomy (n = 161) and distal gastrectomy (n = 51). Overall, 38 (17.9%) patients failed to complete the program, with no mortality. Univariable analysis (P < 0.15) revealed that ERP failure was associated with age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) grade, tumor location, preoperative education, combined operation, long operation time, and significant blood loss. Multivariable analysis (P < 0.05) showed that age, ASA grade III, combined operation and preoperative education were independent risk factors for ERP failure. CONCLUSIONS: We showed that an advanced age, a high ASA grade, lack of a preoperative education and combined surgery were independent risk factors associated with ERP failure after laparoscopic gastrectomy. Therefore, a preoperative patient evaluations and education are important for the success of ERPs.

Low-grade gangliogliomas in adults: A population-based study.

BACKGROUND: Low-grade gangliogliomas (GGs) are rare tumors of the central nervous system in adults. This study aims to define their characteristics, prognostic factors, and the impact of different treatment patterns on survival. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to investigate the potential clinicopathological factors of low-grade GGs in adult patients (age ≥18 years). Kaplan-Meier method and Cox regression model were utilized to evaluate the associations between variables and overall survival (OS). RESULTS: A total of 703 adult patients diagnosed with low-grade GGs were identified between 2004 and 2016, with a median follow-up period of 60.0 months. The median age at diagnosis was 32.0 years, with 50.1% of patients being male, 84.2% white people, and 40.2% of married status. The predominant tumor site was located in temporal lobe (38.8%). The median OS time for the whole cohort was not reached. The 5- and 10-year OS rates for patients underwent gross total resection (GTR) were 92.5% and 87.2%, respectively. Univariate and multivariate analysis showed age, gender, tumor site, and treatment pattern were significant factors for OS. The employment of adjuvant radiotherapy (RT) and/or chemotherapy would significantly shorten OS time. CONCLUSIONS: This is the largest retrospective study of adult low-grade GGs up to date. Younger age, female gender, temporal lobe location, and GTR indicated better survival. Adjuvant RT and/or chemotherapy should not be considered after whatever surgery in adult patients with low-grade GGs, unless the malignant transformation has been confirmed.

USP25 Expression in Peripheral Blood Mononuclear Cells Is Associated With Bone Mineral Density in Women.

Osteoporosis is the most common metabolic bone disease in postmenopausal women. As precursors of osteoclasts, peripheral blood mononuclear cells are accessible and considered suitable models for studying osteoporosis pathology. Ubiquitination is a crucial protein degradation system in bone metabolism. The aim of this study was to identify potential ubiquitination-related genes in PBMCs that are related to osteoporosis pathogenesis. Therefore, we performed an integrated analysis of osteoporosis-related microarray datasets. With the obtained ubiquitination-related gene set, weighted gene coexpression network analysis was performed. The results showed that genes in the turquoise module were correlated with menopause, and 48 genes were identified as hub genes. A differential expression analysis revealed 43 differentially expressed genes between pre- and postmenopausal samples. After integrating the information on differentially expressed menopause-related genes, we found that several members of the ubiquitin-specific protease (USP) family (USP1, USP7, USP9X, USP16, and USP25) were highly expressed in samples from postmenopausal female and that, USP25 expression was significantly higher in low-BMD samples than in high-BMD samples among samples from premenopausal subjects (p = 0.0013) and among all samples (p = 0.013). Finally, we verified the protein expression of USP25 in PBMCs by performing Western blot analysis, which yielded results consistent with the aforementioned results. Moreover, by assessing GTEx datasets, we found that USP25 expression was highly correlated with TRAF6 expression in whole blood (p < 0.001). We also tested the protein expression levels of TRAF6 in PBMCs and found that it was positively correlated with USP25 expression (p = 0.036). Our results reveal that the ubiquitin-specific protease family may play important roles in menopause and that USP25 is related to osteoporosis pathogenesis.

Impact of homogeneous and heterogeneous risk factors on the incidence and prognosis of brain metastases in patients with hepatocellular carcinoma.

BACKGROUND: This study aimed to identify the incidence, risk factors, and survival outcome associated with brain metastases (BM) in hepatocellular carcinoma (HCC) patients using a large-scale population-based cancer registry database. METHODS: Between 2010 and 2016, patients with BM from HCC were included using the Surveillance, Epidemiology, and End Results (SEER) program. The risk and prognostic factors for BM were recognized by multivariate logistic and Cox regression model analysis. The overall survival (OS) and cancer-specific survival (CSS) of HCC patients with BM were assessed using Kaplan-Meier curves with log-rank tests. RESULTS: A total of 141 (0.33%) HCC patients detected with BM were included for analysis. Younger age, tumor pathological undifferentiation, no surgery, radiation therapy, no chemotherapy, synchronous bone, or lung metastases were positively associated with BM in the HCC cohort. The median OS and CSS of the BM patients were 3 months, while the corresponding survival time in HCC patients without BM was 13 and 23 months. Black race, tumor pathological undifferentiation, absence of chemotherapy, and concomitant lung metastases were independently associated with the worse survival. CONCLUSIONS: Although the overall prognosis of patients with BM from HCC was extremely poor, a list of homogeneous and heterogeneous risk factors were found to be significantly associated with the occurrence and prognosis of BM in HCC patients. These relevant factors may provide more valuable references for individualized treatment in clinical practice.

Effect of HUK on the outcome of ruptured intracranial aneurysm.

OBJECTIVE: To evaluate the clinical efficacy of Human Urinary Kallidinogenase (HUK) on the outcome of patients with ruptured intracranial aneurysm. METHODS: This was a prospective, open-label study. At the Department of Neurosurgery in our hospital, 127 patients were treated and operated due to ruptured intracranial aneurysm in the period 2015-2016. After surgery, all the patients received basic treatment and 70 patients received additional HUK treatment (HUK group) according to their willing. In detail, 0.15 PNA unit of HUK injection plus 100 ml saline in intravenous infusion was performed, with once a day for 14 consecutive days. The modified Rankin Scale (mRS) scores and favorable mRS rates (mRS 0-1) were analyzed 3-month after the treatment. RESULTS: No difference was shown in the basic characteristics between the two groups (p > 0.05). Favorable mRS rate in the HUK group (71.43%) was significantly higher than that in control group (50.88%, p < 0.05). In addition, 3-month death rate was significantly lower in the HUK group. Delayed ischemic stroke rate was similar between the two groups. CONCLUSION: HUK can reduce morbidity and mortality of patients with ruptured intracranial aneurysm after surgery.

Highly Efficient Glioma Targeting of Tat Peptide-TTA1 Aptamer-Polyephylene Glycol-Modified Gelatin-Siloxane Nanoparticles.

Gliomas are the most common type of intracranial malignant tumor; however, current treatment approaches are often ineffective due to limited penetration of genes or drugs through the blood-brain barrier (BBB). Here we describe the synthesis of gelatin-siloxane nanoparticles (GS NPs) as candidate gene carriers through a two-step sol-gel process. To increase the efficiency of glioma targeting, human immunodeficiency virus-derived Tat, tumor-targeting aptamer (TTA)1, and polyethylene glycol (PEG) were conjugated to the GS NPs to generate Tat-TTA1-PEG-GS NPs. In vivo imaging revealed that these modified NPs not only evaded capture by the reticulo-endothelial system, but were able to cross the BBB to reach gliomas. Our results suggest that Tat-TTA1-PEG-GS NPs are a new type of non-viral vector that can deliver therapeutic DNA or drugs for highly efficient glioma treatment.

Regulation of human glioma cell apoptosis and invasion by miR-152-3p through targeting DNMT1 and regulating NF2 : MiR-152-3p regulate glioma cell apoptosis and invasion.

BACKGROUND: MiRNAs are involved in aberrant DNA methylation through regulation of DNA methyltransferases (DNMTs) in the pathogenesis and progression of glioblastomas (GBM). MiR-152-3p was down-expressed in human malignancies, and served as a tumor suppressor. Neurofibromatosis type 2 (NF2) was significantly decreased in GBM tissues with a high level of methylation. However, the link between miR-152-3p, DNMT1 and methylation of NF2 in GBM is not clearly established. This study was conducted to detect the mechanism between miR-152-3p, DNMT1 and NF2 in GBM. METHODS: The levels of DNMT1 and NF2 expression were studied by qRT-PCR, Western blot, immunofluorescence, and immumohistochemical staining. Methylation in the promoter region of NF2 was detected by methylation-specific PCR and bisulfate genomic sequencing PCR. Cell proliferation was examined by Cell-Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assay, and cell invasion was evaluated by transwell assay. Flow cytomery and Hoechst staining were used to analyze cell apoptosis. A dual luciferase system was used to confirm the relationship between miR-152-3p and DNMT1. RESULTS: Methylation of NF2 and DNMT1 was markedly increased, and miR-152-3p was downregulated in GBM tissues and glioma cells. Both knockdown of DNMT1 and overexpression miR-152-3p showed that demethylation activated the expression of NF2. Furthermore, miR-152-3p directly targeted DNMT1. Both miR-152-3p overexpression and DNMT1 knockdown significantly induced cell apoptosis and inhibited invasive activity. This was also observed after NF2 overexpression. CONCLUSIONS: These results indicated that miR-152-3p can inhibit glioma cell proliferation and invasion activities by decreasing DNMT1. The restoration of miR-152-3p may have therapeutic application in the treatment of GBM.

Tat peptide-decorated gelatin-siloxane nanoparticles for delivery of CGRP transgene in treatment of cerebral vasospasm.

BACKGROUND: Gene transfer using a nanoparticle vector is a promising new approach for the safe delivery of therapeutic genes in human disease. The Tat peptide-decorated gelatin-siloxane (Tat-GS) nanoparticle has been demonstrated to be biocompatible as a vector, and to have enhanced gene transfection efficiency compared with the commercial reagent. This study investigated whether intracisternal administration of Tat-GS nanoparticles carrying the calcitonin gene-related peptide (CGRP) gene can attenuate cerebral vasospasm and improve neurological outcomes in a rat model of subarachnoid hemorrhage. METHOD: A series of gelatin-siloxane nanoparticles with controlled size and surface charge was synthesized by a two-step sol-gel process, and then modified with the Tat peptide. The efficiency of Tat-GS nanoparticle-mediated gene transfer of pLXSN-CGRP was investigated in vitro using brain capillary endothelial cells and in vivo using a double-hemorrhage rat model. For in vivo analysis, we delivered Tat-GS nanoparticles encapsulating pLXSN-CGRP intracisternally using a double-hemorrhage rat model. RESULTS: In vitro, Tat-GS nanoparticles encapsulating pLXSN-CGRP showed 1.71 times higher sustained CGRP expression in endothelial cells than gelatin-siloxane nanoparticles encapsulating pLXSN-CGRP, and 6.92 times higher CGRP expression than naked pLXSN-CGRP. However, there were no significant differences in pLXSN-CGRP entrapment efficiency and cellular uptake between the Tat-GS nanoparticles and gelatin-siloxane nanoparticles. On day 7 of the in vivo experiment, the data indicated better neurological outcomes and reduced vasospasm in the subarachnoid hemorrhage group that received Tat-GS nanoparticles encapsulating pLXSN-CGRP than in the group receiving Tat-GS nanoparticles encapsulating pLXSN alone because of enhanced vasodilatory CGRP expression in cerebrospinal fluid. CONCLUSION: Overexpression of CGRP attenuated vasospasm and improved neurological outcomes in an experimental rat model of subarachnoid hemorrhage. Tat-GS nanoparticle-mediated CGRP gene delivery could be an innovative strategy for treatment of cerebral vasospasm after subarachnoid hemorrhage.

[Research on Tat peptide-polyethylene glycol modified gelatin-siloxane nanoparticles across the blood-brain barrier].

Gelatin-siloxane nanoparticles (GS NPs) have been considered to be good gene carrier candidate in vitro, since they have several advantages such as low toxicity, easy preparation and surface modification. In this study, the Tat-PEG-GS NPs were synthesized by the gelatin-siloxane, surface-modified with the polyethylene glycol (H2 N-PEG-COOH) and Tat peptide (KYGRRRQRRKKRGC) and thus constructed a delivery system which can cross BBB (Blood-brain barrier). The morphology, diameter, and zeta potential of Tat-PEG-GS NPs carrier system were characterized with transmission electron microscopy (TEM) and Nano-ZS zetasizer dynamic light scattering Detector. The organ distribution and dynamic evolution localized in the brain parenchyma of Tat-PEG-GS NPs in vivo was investigated with Cri in vivo imaging system and TEM. The obtained Tat-PEG-GS NPs were approximately spherical in shape with average particle size of 150-200 nm and zeta potentials of (32.27 +/- 2.47) mV. In vivo imaging results showed that the accumulation of Tat-PEG-GS NPs was higher in the brain than the accumulation of PEG-GS NPs, but the accumulation of Tat-PEG-GS NPs was lower in the liver than the accumulation of PEG-GS NPs. These differences are statistically significant. The nanocomplex could cross the BBB and reach the neural tissues tested with TEM. The Tat-PEG-GS NPs could cross the BBB and escape the arrest of the reticuloendothelial system (RES), and it would be potential nano-carrier systems for central delivery.

In vitro and in vivo studies on gelatin-siloxane nanoparticles conjugated with SynB peptide to increase drug delivery to the brain.

BACKGROUND: Nanobiotechnology can provide more efficient tools for diagnosis, targeted and personalized therapy, and increase the chances of brain tumor treatment being successful. Use of nanoparticles is a promising strategy for overcoming the blood-brain barrier and delivering drugs to the brain. Gelatin-siloxane (GS) nanoparticles modified with Tat peptide can enhance plasmid DNA transfection efficiency compared with a commercial reagent. METHODS: SynB-PEG-GS nanoparticles are membrane-penetrable, and can cross the blood-brain barrier and deliver a drug to its target site in the brain. The efficiency of delivery was investigated in vivo and in vitro using brain capillary endothelial cells, a cocultured blood-brain barrier model, and a normal mouse model. RESULTS: Our study demonstrated that both SynB-PEG-GS and PEG-GS nanoparticles had a spherical shape and an average diameter of 150-200 nm. It was shown by MTT assay that SynB-PEG-GS nanoparticles had good biocompatibility with brain capillary endothelial cells. Cellular uptake by SynB-PEG-GS nanoparticles was higher than that for PEG-GS nanoparticles for all incubation periods. The amount of SynB-PEG-GS nanoparticles crossing the cocultured blood-brain barrier model was significantly higher than that of PEG-GS nanoparticles at all time points measured (P < 0.05). In animal testing, SynB-PEG-GS nanoparticle levels in the brain were significantly higher than those of PEG-GS nanoparticles at all time points measured (P < 0.01). In contrast with localization in the brain, PEG-GS nanoparticle levels were significantly higher than those of SynB-PEG-GS nanoparticles (P < 0.01) in the liver. CONCLUSION: This study indicates that SynB-PEG-GS nanoparticles have favorable properties with regard to morphology, size distribution, and toxicity. Moreover, the SynB-PEG-GS nanoparticles exhibited more efficient brain capillary endothelial cell uptake and improved crossing of the blood-brain barrier. Further, biodistribution studies of rhodamine-loaded nanoparticles demonstrated that modification with the SynB peptide could not only improve the ability of PEG-GS nanoparticles to evade capture in the reticuloendothelial system but also enhance their efficiency in crossing the blood-brain barrier.

[Repairing front skull base and saddle bottom of cerebrospinal fluid rhinorrhea under endoscopy].

OBJECTIVE: To explore the methods and techniques of repairing cerebrospinal fluid (CSF) rhinorrhea and reconstructing the defects of skull base under endoscopy. METHODS: The clinical data of 26 patients undergoing endoscopic repair of CSF rhinorrhea were analyzed retrospectively. There were 19 males and 7 females with an average age of 31.5 years old. Rhinorrhea was classified into 4 types: ethmoidal sinus type (n = 6), sphenoid sinus type (n = 14) and mixed type (n = 6) and frontal sinus type (n = 0). RESULTS: The causes of rhinorrhea were as follows: traumatic leakage (n = 17), post-operative breakage of saddle area (n = 6), damage after endonasal surgery (n = 2) rhinorrhea after gamma-knife for pituitary (n = 1). All cases were successfully repaired via an endoscopic endonasal approach. Among them, 22 patients were repaired only once while 4 patients with recurrent CSF rhinorrhea were repaired again. The follow-up period was from 6 months to 4 years. And satisfactory outcomes were achieved in all. CONCLUSION: Accurate localization of CSF leakage, reliable reconstruction of skull base, secure fixation of adhesive materials and continuous lumbar CSF drainage are keys surgical techniques. Endoscopic repair of front skull base and saddle bottom of CSF rhinorrhea is a reliable, effective and mini-invasive surgical approach worth further popularization.