Identification of the principal neuropeptide MIP and its action pathway in larval settlement of the echiuran worm Urechis unicinctus.

BACKGROUND: Larval settlement and metamorphosis represent critical events in the life history of marine benthic animals. Myoinhibitory peptide (MIP) plays a pivotal role in larval settlement of marine invertebrates. However, the molecular mechanisms of MIP involved in this process are not well understood. RESULTS: In this study, we evaluated the effects of thirteen MIP mature peptides on triggering the larval settlement of Urechis unicinctus (Xenopneusta, Urechidae), and determined that MIP2 was the principal neuropeptide. Transcriptomic analysis was employed to identify differentially expressed genes (DEGs) between the MIP2-treated larvae and normal early-segmentation larvae. Both cAMP and calcium signaling pathways were enriched in the DEGs of the MIP2-treated larvae, and two neuropeptide receptor genes (Spr, Fmrfar) were up-regulated in the MIP2-treated larvae. The activation of the SPR-cAMP pathway by MIP2 was experimentally validated in HEK293T cells. Furthermore, fourteen cilia-related genes, including Tctex1d2, Cfap45, Ift43, Ift74, Ift22, Cav1 and Mns1, etc. exhibited down-regulated expression in the MIP2-treated larvae. Whole-mount in situ hybridization identified two selected ciliary genes, Tctex1d2 and Cfap45, were specially expressed in circumoral ciliary cells of the early-segmentation larvae. Knocking down Tctex1d2 mRNA levels by in vivo RNA interference significantly increased the larval settlement rate. CONCLUSION: Our findings suggest that MIP2 inhibits the function of the cilia-related genes, such as Tctex1d2, through the SPR-cAMP-PKA pathway, thereby inducing larval settlement in U. unicinctus. The study contributes important data to the understanding of neuropeptide regulation in larval settlement.

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.

Flow Diverter Device-Assisted Coiling Treatment for Cerebral Blister Aneurysm: A Single-Center Study.

Although endovascular treatment is a promising approach, blood blister-like aneurysms (BBAs) still present treatment challenges. This study aimed to assess the effectiveness and safety of flow diverter device-assisted coiling (FDDAC) for the treatment of BBAs, which are broad based and friable with a high rebleeding risk. Eight patients (five females and three males) who presented with subarachnoid hemorrhages (SAH) due to BBA ruptures between May 2020 and May 2022 were retrospectively enrolled. All patients were treated by flow diverter device (Tubridge) adjunctive coil embolization using a semi-deploying technique. The demographic information, angiographic data, interval between admission and treatment, materials, therapy, clinical outcomes (including periprocedural and intraprocedural mortality and morbidity), and follow-up results of all patients were reviewed. The mean age of the patients with BBAs was 48.5 years (range 31-62 years); aneurysm sizes ranged from 2.2 × 1.7 mm to 4.6 × 3.2 mm, and the median Hunt-Hess score was 3. All aneurysms were completely closed at follow-up, and all 8 patients had excellent clinical outcomes (modified Rankin scores = 0-2) at discharge. Angiograms showed complete aneurysm occlusion after 6 months to 1 year. In addition, there were no cases of re-rupture, re-treatment, or recurrence of the aneurysms. FDDAC is safe to use in patients with BBAs and provides an alternative treatment option for this disease.

Complex torcular dural arteriovenous fistula leading to cortical venous reflux-induced severe varix and subsequent bilateral cerebral hemispheric hemorrhage: a case report.

Background and importance: Dural arteriovenous fistulas (dAVFs) with cortical venous reflux (CVR) are associated with a higher incidence of intracranial hemorrhage (ICH). We report a rare case of a complex torcular dAVF with severe cortical veins (CV) varix leading to extensive bilateral cerebral hemorrhages. This discovery suggests a potential new subtype of dAVF. The case underscores the necessity of a comprehensive understanding of hemodynamic changes in dAVFs and the importance of considering venous compensatory capacity in treatment. This case challenges existing classifications and treatment strategies for dAVFs, highlighting the need for further research and discussion within the neurosurgical community. Clinical presentation: A 56-year-old male was admitted to the hospital presenting with dizziness, fatigue, and numbness. Brain CT scans revealed extensive bilateral cerebral hemorrhages. Digital subtraction angiography (DSA) identified a complex torcular dAVF. No cerebral sinus venous thrombosis was detected, but a venous variation in the left transverse sinus was observed. Preoperative DSA demonstrated the patient's well-developed venous compensatory ability. Subsequently, the patient underwent transarterial embolization. The patient made a good recovery. Follow-up DSA and MR angiography at 3 months and 1 year post-treatment showed no recurrence. Conclusion: DAVFs are rare lesions, prone to ICH, particularly when CVR is involved. We report a rare case of CVR with severe varix leading to hemorrhagic lesions in both cerebral hemispheres. Our aim is to alert neurosurgical colleagues worldwide to this potential new subtype and to evaluate treatment options, in order to assist those who may encounter such cases in the future.

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.

Rivaroxaban triggered multifocal intratumoral hemorrhage of the cabozantinib-treated diffuse brain metastases: A case report and review of literature.

Brain metastases (BMs) are the most common intracranial malignancy with poor prognosis. Patients with intracranial tumors are at greater risk for thrombotic complications and intracranial hemorrhage. Rivaroxaban is a potent oral anticoagulant with the high selectivity of direct factor Xa inhibition. The incidence and severity of rivaroxaban-triggered intratumoral hemorrhage (ITH) in patients with BMs remain unknown. A 57-year-old woman was diagnosed with multiple lung, bone, and BMs from unknown primary cancer origin, and refused any invasive procedures to confirm tumor pathology. However, this patient had a relatively favorable outcome after treating with cabozantinib, an inhibitor of multiple tyrosine kinases. The patient survived over 2 years and developed deep vein thrombosis of right lower limb. Oral rivaroxaban was prescribed, and the multifocal catastrophic ITH was encountered after 1 week. The last head computed tomography imaging revealed a rare but typical image of diffuse hemorrhagic metastases. Hemorrhagic-prone BMs, therapeutic rivaroxaban, and cabozantinib treatment increase risks to develop ITH. In this case rivaroxaban was the trigger to this terminal event. This case is a miserable lesson and keeps reminding us to stay vigilant in clinical practice even when there is a potential benefit for anticoagulation in such population.

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.

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.

Premature MicroRNA-Based Therapeutic: A "One-Two Punch" against Cancers.

Up-to-date knowledge regarding the biogenesis and functioning of microRNAs (miRNAs) has provided a much more comprehensive and concrete view of miRNA biology than anyone ever expected. Diverse genetic origins and biogenesis pathways leading to functional miRNAs converge on the synthesis of ≈21-nucleotide RNA duplex, almost all of which are processed from long premature sequences in a DICER- and/or DROSHA-dependent manner. Formerly, it was assumed that one mature strand of the duplex is preferentially selected for entry into the silencing complex, and the paired passenger strands (miRNA*) are subjected to degradation. However, given the consolidated evidence of substantial regulatory activity of miRNA* species, currently, this preconception has been overturned. Here, we see the caveat and opportunity toward exogenously manipulating the expression of premature miRNA, leading to simultaneous upregulation or downregulation of dual regulatory strands due to altered expressions. The caveat is the overlooked miRNA* interference while manipulating the expression of a target miRNA at the premature stage, wherein lies the opportunity. If the dual strands of a pre-miRNA function synergistically, the overlooked miRNA* interference may inversely optimize the therapeutic performance. Insightfully, targeting the premature miRNAs may serve as the "one-two punch" against diseases, especially cancers, and this has been discussed in detail in this review.

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.

[LVIS stent-assisted coil embolization in the acute stage of ruptured intracranial aneurysms].

OBJECTIVE: To evaluate the safety and efficacy of LVIS stent-assisted coil embolization in the acute phase of ruptured intracranial aneurysms. METHODS: The clinical data of 55 patients with ruptured intracranial aneurysm treated with LVIS stent-assisted coil embolization admitted to Zhongshan Hospital of Xiamen University from January 2016 to December 2018 were analyzed retrospectively. The general data, the characteristics of aneurysms and the occurrence of perioperative complications of the patients were collected. The clinical prognosis of the patients at discharge and 6 months of follow-up was recorded. The Glasgow prognosis score (GOS) was graded as good (5), average (3-4), and poor (1-2), and the cerebral angiography results were recorded immediately after embolization and 6-month follow-up. The aneurysm occlusion was assessed by Raymond grade, Raymond I was complete obliteration, II was residual neck and III was residual aneurysm. RESULTS: All 55 patients received LVIS stent-assisted coil embolization within 72 hours of ruptured intracranial aneurysms, and all stents were released successfully, including 16 males (29.1%) and 39 females (70.9%). The median age was 53 (24-80) years old. Anterior circulation aneurysms were found in 49 patients (89.1%) and posterior circulation aneurysms in 6 patients (10.9%). According to Hunt-Hess classification, there were 43 patients with grade I-II (78.2%), 7 patients with grade III (12.7%) and 5 patients with grade IV-V (9.1%). The first digital subtraction angiography (DSA) examination of 55 patients after embolization showed that 41 patients had complete obliteration of aneurysms and 14 had residual neck; and the smaller the aneurysm was, the higher the rate of complete obliteration after embolization was. The proportion of small aneurysms (maximum diameter ≤ 7 mm) in the complete obliteration group was significantly higher than that in the neck residual group (100.0% vs. 64.3%, P < 0.01). Among the 55 patients, there was 1 patient suffered from in-stent thrombosis during embolization, 1 patient suffered from distal vascular thrombosis induced by plaque shedding during embolization, 1 patient suffered from vasospasm during embolization, and 1 patient suffered from postoperative distal cerebral hemorrhage after embolization. In 2 dead patients, 1 died of cardiogenic disease and 1 died of respiratory failure caused by severe pneumonia. At discharge, the prognosis was good in 40 patients, average in 10 patients, and poor in 5 patients; and the higher the Hunt-Hess grade at admission, the worse the prognosis. The proportion of patients with Hunt-Hess grade I-II at admission in the good prognosis group was significantly higher than that in the general prognosis group and the poor prognosis group (90.0% vs. 50.0%, 40.0%, P < 0.01). Of the 55 patients, 39 completed clinical prognosis and cerebral angiography 6 months after embolization for follow-up. All patients had GOS no less than 3, including 32 patients with complete obliteration of aneurysm, 4 with residual neck and 3 with residual aneurysm. The smaller the aneurysm, the higher the rate of complete obliteration at 6-month follow-up was. The proportion of small aneurysm in the complete obliteration group was significantly higher than that in the residual neck group and the residual aneurysm group (100.0% vs. 75.0%, 33.3%, P < 0.01). There was no rebleeding or ischemic complication at 6-month follow-up. CONCLUSIONS: LVIS stent assisted coil embolization is safe, effective and feasible in the acute stage of ruptured intracranial aneurysms. Standardizing antiplatelet therapy and dense packing of aneurysms during embolization are the key to reduce bleeding and ischemic complications.

Automated fiducial marker detection and fiducial point localization in CT images for lung biopsy image-guided surgery systems.

In the lung biopsy image-guided surgery systems, the fiducial markers are used for point-based registration of the patient space to the CT image space. Fiducial marker detection and fiducial point localization in CT images have great influence on the accuracy of registration and guidance. This study proposes a fiducial marker detection approach based on the features of marker image slice sequences and a fiducial point localization approach according to marker projection images, without depending on the priori-knowledge of the marker default parameters provided by the manufacturers. The accuracy of our method was validated based on a CT image dataset of 24 patients. The experimental results showed that all 144 markers of 24 patients were correctly detected, and the fiducial points were localized with the average error of 0.35 mm. In addition, the localization accuracy of the proposed method was improved by an average of 12.5% compared with the accuracy of the previous method using the marker default parameters provided by the manufacturers. Thus, the study demonstrated that the proposed detection and localization methods are accurate and robust, which is quite encouraging to meet the requirement of future clinical applications in the image guided lung biopsy and surgery systems.

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.

Enhancement of hypothalamic STAT3 acetylation by nuclear receptor Nur77 dictates leptin sensitivity.

Leptin, an anorexigenic hormone in the hypothalamus, suppresses food intake and increases energy expenditure. Failure to respond to leptin will lead to obesity. Here, we discovered that nuclear receptor Nur77 expression is lower in the hypothalamus of obese mice compared with normal mice. Injection of leptin results in significant reduction in body weight in wild-type mice but not in Nur77 knockout (KO) littermates or mice with specific Nur77 knockdown in the hypothalamus. Hypothalamic Nur77 not only participates in leptin central control of food intake but also expands leptin's reach to liver and adipose tissues to regulate lipid metabolism. Nur77 facilitates signal transducer and activator of transcription 3 (STAT3) acetylation by recruiting acetylase p300 and disassociating deacetylase histone deacetylase 1 (HDAC1) to enhance the transcriptional activity of STAT3 and consequently modulates the expression of downstream gene Pomc in the hypothalamus. Nur77 deficiency compromises response to leptin in mice fed a high-fat diet. Severe leptin resistance in Nur77 KO mice with increased appetite, lower energy expenditure, and hyperleptinemia contributes to aging-induced obesity. Our study opens a new avenue for regulating metabolism with Nur77 as the positive modulator in the leptin-driven antiobesity in the hypothalamus.

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.

Synthesis and characterization of NIR-responsive Aurod@pNIPAAm-PEGMA nanogels as vehicles for delivery of photodynamic therapy agents.

A near-infrared (NIR)-responsive Aurod@pNIPAAm-PEGMA nanogel was synthesized in two steps, growing a PEGMA monolayer on the surface of gold nanorods (AuNRs), followed by in situ polymerization and cross-linking of N-iso-propylacrylamide (NIPAAm) and poly-(ethylene glycol)-methacrylate (PEGMA). The AuNRs and Aurod@pNIPAAm-PEGMA nanogel were characterized by UV-vis spectroscopy, Raman spectroscopy, Fourier transform infrared spectroscopy, and transmission electron microscopy, respectively. The lower critical solution temperature of the Aurod@pNIPAAm-PEGMA nanogel could be tuned by changing the molar ratio of NIPAAm/PEGMA. The NIR-mediated drug release behavior of the Aurod@pNIPAAm-PEGMA nanogel was studied with zinc phthalocyanines (ZnPc4) as a drug model. It was also demonstrated that the loaded ZnPc4 could keep the capability of generating singlet oxygen, and the in vitro study showed a great photodynamic therapy (PDT) effect on Hela cells. It thus indicated the potential of this Aurod@pNIPAAm-PEGMA nanogel for application as a drug carrier in PDT, which might make contributions to oncotherapy.

Multifunctional ZnPc-loaded mesoporous silica nanoparticles for enhancement of photodynamic therapy efficacy by endolysosomal escape.

The cellular uptake and localization of photosensitizer-loaded nanoparticles have significant impact on photodynamic therapy (PDT) efficacy due to short lifetime and limited action radius of singlet oxygen. Herein, we develop poly(ethylene glycol) (PEG)- and polyethylenimine (PEI)-functionalized zinc(II) phthalocyanine (ZnPc)-loaded mesoporous silica nanoparticles (MSNs), which are able to distribute in the cytosol by endolysosomal escape. In this photosensitizer-carrier system (PEG-PEI-MSNs/ZnPc), ZnPc is a PDT agent; MSNs are the nanocarrier for encapsulating ZnPc; PEI facilitates endosomal escape; and PEG enhances biocompatibility. The as-synthesized PEG-PEI-MSNs/ZnPc have a high escape efficiency from the lysosome to the cytosol due to the "proton sponge" effect of PEI. Compared with the ZnPc-loaded MSNs, the phototoxicity of the PEG-PEI-MSNs/ZnPc is greatly enhanced in vitro. By measuring the mitochondrial membrane potential, a significant loss of >80% Δψm after treatment with PEG-PEI-MSNs/ZnPc-PDT is observed. It is further demonstrated that the ultra-efficient passive tumor targeting and excellent PDT efficacy are achieved in tumor-bearing mice upon intravenous injection of PEG-PEI-MSNs/ZnPc and the followed light exposure. We present here a strategy for enhancement of PDT efficacy by endolysosomal escape and highlight the promise of using multifunctional MSNs for cancer therapy.