TREM2 Alleviates Subarachnoid Hemorrhage-Induced Brain Injury through Attenuating Neuroinflammation and Programmed Cell Death in Vivo and in Vitro.

BACKGROUND: Apoptosis and pyroptosis are two types of programmed cell death related to the neuroinflammatory reaction after subarachnoid hemorrhage (SAH). Research indicates that triggering receptor expressed on myeloid cells 2 (TREM2) can regulate the SAH-induced inflammatory response. However, whether TREM2 regulates programmed cell death (apoptosis and pyroptosis) remains to be clarified. The purpose of the present study was to investigate the effects of TREM2 on cell death in SAH. METHODS: SAH was induced in adult male C57BL/6J mice by endovascular perforation. An in-vitro cellular model of SAH was established by treating cocultured BV2 microglia and HT22 neuronal cells with oxyhemoglobin. TREM2 overexpression or knockdown was carried out by intraventricular lentivirus injection at 7 d before SAH induction in mice or lentiviral transfection, respectively. Neurobehavioral tests as well as western blot, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunofluorescence, Evans blue (EB) staining, Nissl staining, and flow cytometry assays were performed to investigate the neuroprotective role of TREM2 after SAH. RESULTS: After SAH, the TREM2 mRNA and protein levels were elevated in SAH mice, exhibiting a peak at 72 h. TREM2 overexpression improved the SAH-induced neurological deficits in mice, while TREM2 knockdown worsened them. In the brains of mice with TREM2 overexpression, less neuronal death and more neuronal survival were detected at 72 h post SAH. Meanwhile, TREM2 overexpression showed an inhibitory effect on microglial activation, neutrophil infiltration, and the expression of cell death marker proteins. Consistent results were obtained in vitro. CONCLUSIONS: Our research indicates the important role of TREM2 on cell death after SAH, suggesting that targeting TREM2 might be an effective approach for treating SAH.

PU.1 promotes development of rheumatoid arthritis via repressing FLT3 in macrophages and fibroblast-like synoviocytes.

OBJECTIVES: To uncover the function and underlying mechanism of an essential transcriptional factor, PU.1, in the development of rheumatoid arthritis (RA). METHODS: The expression and localisation of PU.1 and its potential target, FMS-like tyrosine kinase 3 (FLT3), in the synovium of patients with RA were determined by western blot and immunohistochemical (IHC) staining. UREΔ (with PU.1 knockdown) and FLT3-ITD (with FLT3 activation) mice were used to establish collagen antibody-induced arthritis (CAIA). For the in vitro study, the effects of PU.1 and FLT3 on primary macrophages and fibroblast-like synoviocytes (FLS) were investigated using siRNAs. Mechanistically, luciferase reporter assays, western blotting, FACS and IHC were conducted to show the direct regulation of PU.1 on the transcription of FLT3 in macrophages and FLS. Finally, a small molecular inhibitor of PU.1, DB2313, was used to further illustrate the therapeutic effects of DB2313 on arthritis using two in vivo models, CAIA and collagen-induced arthritis (CIA). RESULTS: The expression of PU.1 was induced in the synovium of patients with RA when compared with that in osteoarthritis patients and normal controls. FLT3 and p-FLT3 showed opposite expression patterns compared with PU.1 in RA. The CAIA model showed that PU.1 was an activator, whereas FLT3 was a repressor, of the development of arthritis in vivo. Moreover, results from in vitro assays were consistent with the in vivo results: PU.1 promoted hyperactivation and inflammatory status of macrophages and FLS, whereas FLT3 had the opposite effects. In addition, PU.1 inhibited the transcription of FLT3 by directly binding to its promoter region. The PU.1 inhibitor DB2313 clearly alleviated the effects on arthritis development in the CAIA and CIA models. CONCLUSIONS: These results support the role of PU.1 in RA and may have therapeutic implications by directly repressing FLT3. Therefore, targeting PU.1 might be a potential therapeutic approach for RA.

Enterprise 2 Stent-Assisted Embolization of Paraclinoid Aneurysms: A Single Center Preliminary Study.

Objective: Enterprise stent has been widely used for assisted embolization in wide-necked aneurysms while delayed ischemia or thromboembolic complications for its incomplete stent apposition. The purpose of this study was to summarize and analyze the clinical experience of using Enterprise 2 (EP2) stent-assisted embolization in the treatment of paraclinoid aneurysms. Methods: From January 2019 to December 2020, the clinical and imaging data of 98 patients with paraclinoid aneurysms treated with EP2 stent-assisted embolization were enrolled retrospectively. Preliminary experience and follow-up outcomes of EP2 stent-assisted embolization of paraclinoid aneurysms were assessed by using the Raymond grade and modified Rankin Scale. Results: Of the 98 aneurysms, all stents were released satisfactorily. The immediate postprocedural angiography revealed a complete occlusion of the aneurysms with 77.55% of the (76/98) patients, and the last follow-up angiograms showed complete occlusion with 83.67% of the (82/98) patients. The average aneurysm size was (4.11 ± 1.25) mm, the aneurysm diameter was (4.41 ± 1.37) mm, the vessel radius was (3.87 ± 0.32) mm, the diameter at the distal of stent was (3.23 ± 0.21) mm, and the proximal was (4.18 ± 0.23) mm. Among the 98 aneurysms, 13 cases had incomplete stent apposition, 3 cases had intraoperative knotting, and the stents were improved post adjusted; 2 cases had vasospasm and 1 case had stenosis during operation, the symptoms were improved after symptomatic treatment. The result demonstrated that stent length and inner bending radius of parent artery were the pivotal factors affecting incomplete stent apposition (P < 0.01). Conclusion: The EP2 stent for the treatment of paraclinoid aneurysms is safe and effective, however, the length of the stent and the inner bending radius of parent artery are important factors affecting incomplete stent apposition.

Safety and effectiveness of double microcatheter technique in the treatment of ruptured aneurysms of anterior cerebral circulation.

Objective: To evaluate the safety and effectiveness of the double microcatheter technique in the treatment of ruptured aneurysms of the anterior cerebral circulation. Methods: Between 2012 and 2019, 113 patients with ruptured aneurysms of the anterior cerebral circulation were treated using the double microcatheter technique. Clinical records, angiographic results, and procedure-related complications were reviewed. Clinical and angiographic follow-up was performed. Results: Complete occlusion, neck remnant, and partial occlusion were, respectively, recorded in 56.6, 38.9, and 4.4% of the total cases. For all patients, the incidence of intraoperative complications was 5.3% (6/113), and the overall rate of morbidity was 10.6% (12/113). Before discharge, three patients (2.7%) died. There was no procedure-related mortality. At discharge, favorable outcomes were observed in 79.6% (90/113) of the patients. High Hunt-Hess grades and receiving a craniotomy or external ventricular drainage were risk factors for clinical outcomes at discharge. Clinical follow-up was performed in 91 patients at a mean interval of 14.07 ± 11.68 months. At follow-up, favorable outcomes were observed in 92.3% (84/91) of the patients. Angiographic follow-up was performed in 66 patients at an average of 11.53 ± 11.13 months. The recurrence rate was 37.9%. Of these patients, 13 (19.7%) received retreatment. Conclusion: The double microcatheter technique can be performed in ruptured aneurysms with high technical success and low morbidity/mortality. However, recurrence remains a problem, and patients should be followed up regularly.

Isoliquiritigenin mitigates oxidative damage after subarachnoid hemorrhage in vivo and in vitro by regulating Nrf2-dependent Signaling Pathway via Targeting of SIRT1.

BACKGROUND: Oxidative stress is a crucial factor leading to subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). Isoliquiritigenin has been verified as a powerful anti-oxidant in a variety of diseases models and can activate sirtuin 1 and nuclear factor-erythroid 2-related factor 2 (Nrf2) pathways. However, the effects of isoliquiritigenin against EBI after SAH and the underlying mechanisms remain elusive. PURPOSE: The primary goal of this study is to verify the therapeutic effects of isoliquiritigenin on EBI after SAH and the possible molecular mechanisms. STUDY DESIGN: A prechiasmatic cistern SAH model in rats and a hemoglobin incubation SAH model in primary neurons were established. Isoliquiritigenin was administered after SAH induction. EX527 was employed to inhibit sirtuin 1 activation and ML385 was used to suppress Nrf2 signaling. METHODS: In our study, neurological scores, brain edema, biochemical estimation, western blotting, and histopathological study were performed to explore the therapeutic action of isoliquiritigenin against SAH. RESULTS: Our data revealed that isoliquiritigenin significantly mitigated oxidative damage after SAH as evidenced by decreased reactive oxygen species overproduction and enhanced intrinsic anti-oxidative system. Concomitant with the reduced oxidative insults, isoliquiritigenin improved neurological function and reduced neuronal death in the early period after SAH. Additionally, isoliquiritigenin administration significantly enhanced Nrf2 and sirtuin 1 expressions. Inhibition of Nrf2 by ML385 reversed the anti-oxidative and neuroprotective effects of isoliquiritigenin against SAH. Moreover, inhibiting sirtuin 1 by EX527 pretreatment suppressed isoliquiritigenin-induced Nrf2-dependent pathway and abated the cerebroprotective effects of isoliquiritigenin. In primary cortical neurons, isoliquiritigenin treatment also ameliorated oxidative insults and repressed neuronal degeneration. The beneficial aspects of isoliquiritigenin were attributed to the promotion of sirtuin 1 and Nrf2 signaling pathways and were counteracted by EX527. CONCLUSION: Our findings suggest that isoliquiritigenin exerts cerebroprotective effects against SAH-induced oxidative insults by modulating the Nrf2-mediated anti-oxidant signaling in part through sirtuin 1 activation. Isoliquiritigenin might be a new potential drug candidate for SAH.

Comparison of Enterprise stent 2 with 1 in assisting coiling of ruptured aneurysms: a real-world study.

Aim: To investigate the effectiveness and safety of the Enterprise 2 (E2) stent versus the Enterprise 1 (E1) stent in treating ruptured intracranial aneurysms (RIAs) in China. Materials & methods: The authors conducted an electronic medical record analysis for patients with RIAs who underwent E1/E2 deployment. The main outcomes were immediate complete occlusion (ICO), patient functional outcomes, complications and aneurysm recurrence. Results: Stent deployment was successful in all patients (E2: 90; E1: 270). ICO and patients with good functional outcomes at discharge were similar between E2 and E1 (80.0% vs 75.1% and 78.7% vs 81.1%, respectively). The E2 group had a significantly lower complication rate compared with the E1 group (7.8% vs 16.4%; odds ratio: 0.36; 95% CI: 0.15-0.91; p = 0.031). By 6 months post-discharge, the two groups had comparable patient functional outcomes and aneurysm recurrence (E2 vs E1: 80.2% vs 81.9% and 13.3% vs 14.9%). Conclusion: Compared with the E1 stent, the E2 stent had similar effectiveness but a lower complication risk in treating RIAs.

Emerging nanotherapeutics alleviating rheumatoid arthritis by readjusting the seeds and soils.

Rheumatoid arthritis (RA) is a complicated autoimmune disease that results in severe joint inflammation, synovial hyperplasia, pannus formation, cartilage and bone destruction, and other RA-associated complications. Although the pathogenesis of RA remains unclear, increasing reports have shown that inflammation-relevant cells and the microenvironment of inflamed joints play a critical role in the formation and aggravation of RA. Recently, numerous nanotherapeutics have been engineered to overcome these intractable challenges by readjusting inflammation-related seeds (endothelial cells, macrophages, neutrophils, antigen-presenting cells, fibroblasts, osteoclasts, T cells, B cells, and chondrocytes) and inflamed soils (NO, cell-free DNA, hypoxia, ROS, and pro-inflammatory cytokines). In this review, we first present a detailed pathogenesis of RA, with an emphasis on the emerging advances in regulating seeds or remodeling soils for RA treatment. We then outline these intelligent therapeutics via synergistic seed-soil adjustment, particularly for spatiotemporally cascade-responsive or all-in-one integrational nanosystems. Finally, we briefly discuss the ongoing challenges and prospects for the clinical development and translation of seed soil-based therapies.

Sorafenib-Loaded PLGA-TPGS Nanosystems Enhance Hepatocellular Carcinoma Therapy Through Reversing P-Glycoprotein-Mediated Multidrug Resistance.

Multidrug resistance (MDR) is a key determinant for hepatocellular carcinoma chemotherapy failure. P-glycoprotein is one of the main causes of MDR by causing drug efflux in tumor cells. In order to solve this thorny problem, we prepared a sorafenib-loaded polylactic acid-glycolic acid (PLGA) - D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoparticles (SPTNs). SPTNs were successfully synthesized through an ultrasonic emulsion solvent evaporation method with a favourable encapsulation efficiency of 90.35%. SPTNs were almost spherical in shape with uniform particle size (215.70 ± 0.36 nm), narrow polydispersity index (0.27 ± 0.02) and negative surface charge (-26.01 ± 0.65 mV). In the cellular uptake assay, the intracellular coumarin-6 (C6) fluorescence of TPGS component-based PLGA nanoparticles (C6-PTNs) was 1.63-fold higher relative to that of PVA component-based PLGA nanoparticles (C6-PVNs). The half-maximal inhibitory concentration and apoptosis ratio of SPTNs against HepG2/MDR cells were 3.90 µM and 75.62%, respectively, which were notably higher than free SF and sorafenib-PLGA-PVA nanoparticles (SPVNs). The anti-drug efflux activities of SPTNs were assessed by the intracellular trafficking assay using verapamil as a P-gp inhibitor. SPTNs could effectively inhibit the drug efflux in tumor cells detected by flow cytometry, and suppressed relative MDR1 gene as well as P-glycoprotein expression in tumor cells. Attributed to the MDR reversion effect of SPTNs, the in vivo antitumor efficacy experiment showed that SPTNs significantly inhibited the tumor growth of HepG2/MDR xenograft-bearing nude mice, and obviously reduced the toxicity against liver and kidney compared with SF treatment. In summary, SPTNs, as highly efficient and safe antitumor nano delivery systems, showed promising potential for hepatocellular carcinoma therapy through reversing P-glycoprotein-mediated MDR. Graphical Abstract.

Risk factors of recurrence after endovascular embolization of posterior communicating artery aneurysms.

BACKGROUND AND OBJECTIVE: To determine the risk factors for recurrence after endovascular embolization of posterior communicating artery aneurysms (PcomA). METHODS: We retrospectively analyzed a cohort of 163 patients harboring 172 PocmAs who were treated with endovascular embolization from January 2019 to December 2020. The patients were divided into recurrence and stable groups depending on outcome. Univariate and logistic regression analyses were performed to determine the potential risk factors of recurrence during follow-up. RESULTS: Of the total 163 patients harboring 172 aneurysms, 107 were treated with simple coil occlusion and 65 were treated with stent-assisted coil embolization. There were significant differences in aneurysm sizes and use of non-stent-assisted coil embolizations between the groups (P < 0.05). The incidence of saccular aneurysm and Raymond grade were significantly higher in the recurrent group than in the stable group (P < 0.01). After variable selection, Raymond grade, aneurysm size, saccular aneurysm and non-stent-assisted coil embolization were included in further analysis. Binary logistic regression analysis revealed significant associations with non-stent-assisted coil embolization (P = 0.007), packing density (P < 0.001) and Raymond grades II (P < 0.001) and III (P = 0.002). CONCLUSION: Non-stent-assisted coil embolization, as well as packing density and Raymond grades II grade III are associated with recurrence after endovascular treatment of PcomA.

Predictors of unfavorable outcome in stent-assisted coiling for symptomatic unruptured intracranial spontaneous vertebral artery dissecting aneurysms (uis-VADAs): results from a multicenter study.

OBJECTIVE: To evaluate predictors of unfavorable outcome in stent-assisted coiling for symptomatic unruptured intracranial spontaneous vertebral artery dissecting aneurysms (uis-VADAs) based on 608 reconstructed lesions in 30 medical centres. METHODS: A total of 608 patients (male:female=479:129; mean age, 53.26±10.26 years) with 608 symptomatic uis-VADAs underwent reconstructive treatments using stent(s) with coils between January 2009 and December 2015. Treatments and predictors of unfavorable outcomes were retrospectively analyzed. RESULTS: Mainly, three methods were used to treat patients with uis-VADAs, including routine single-stent in 208 patients (such as Enterprise and others), new low-profile LVIS single stent in 107 patients, and multiple stents in 293 patients. During the median 66 months of clinical follow-up, 14 patients died, and 16 of the remaining 594 survivors had unfavorable outcomes (modified Rankin Scale score 3-5). The overall mortality rate was 2.3% (14/608), and the unfavorable outcome (mRS score 3-6) rate was 4.9% (30/608). Multivariate logistic regression analysis indicated that preprocedural ischemic infarctions (OR=3.78; 95% CI 1.52 to 9.40; p<0.01), diabetes mellitus (OR=3.74; 95% CI 1.31 to 10.68; p=0.01), and procedural complications (OR=14.18; 95% CI 5.47 to 36.80; p<0.01) were predictors of unfavorable outcome in the reconstructed VADAs. CONCLUSIONS: This multicenter study indicated that preprocedural ischemic infarctions, diabetes mellitus, and procedural complications were related to unfavorable clinical outcomes in the reconstructed uis-VADAs.

Hemodynamic Characteristics Associated with Recurrence of Middle Cerebral Artery Bifurcation Aneurysms After Total Embolization.

OBJECTIVE: Hemodynamic parameters are associated with the recurrence of intracranial aneurysms (IAs). Studies showed that high velocity and wall shear stress (WSS) were associated with IAs recurrence after endovascular treatment; nevertheless, factors such as small sample size, locations of IAs, and types of IAs (ie, sidewall or bifurcation) were neglected. The purpose of this study was to identify the hemodynamic characteristics associated with recurrence of middle cerebral artery bifurcation aneurysms (MCABAs) after total embolization by the method of computer fluid dynamics (CFD). METHODS: Following inclusion criteria, we included 92 MCABAs treated with coils only after total embolization from January 2014 to January 2019. We segmented into recurrent and non-recurrent groups according to follow-up digital subtraction angiography (DSA). The MCABA models, including pre-operatively and immediate post-operatively, were reconstructed using 3D-DSAs. The hemodynamic parameters pre-operatively and immediately post-operatively between the groups were calculated and analyzed. RESULTS: There were no significant differences between the recurrent and non-recurrent groups for spatially averaged wall shear stress (SAWSS), maximum wall shear stress (MWSS), velocity, or oscillatory shear index (OSI) at the neck pre-operatively. In the recurrent group, the WSS (22.02±5.11 vs 37.43±8.27 pa, p < 0.001), MWSS (42.59±17.02 vs 66.98±18.61 pa, p=0.014), velocity (0.86±0.19 vs 1.44±0.61 m/s, p=0.01) preoperatively were significantly higher than postoperative values. By contrast, in the non-recurrent group, the WSS (26.53±8.18 vs 22.29±8.64pa, p=0.002), MWSS (42.71±14.01 vs 37.15±15.56 pa, p=0.013), velocity (1.08±0.43 vs 0.23 (0.52, 0.57) m/s, p < 0.001) postoperatively were significantly lower than preoperative values. The OSI, whether in the recurrent group or the non-recurrent group, did not differ significantly between groups (p=0.79 and p=0.19). CONCLUSION: Higher WSS (SAWSS, MWSS) and flow velocity at the aneurysm neck after embolization might be related to recurrence of bifurcation IAs. These might be applied to clinical post-embolization management for the evaluation of bifurcation IAs recanalization.

Smart Nanogatekeepers for Tumor Theranostics.

Nanoparticulate drug delivery systems (nano-DDSs) are required to reliably arrive and persistently reside at the tumor site with minimal off-target side effects for clinical theranostics. However, due to the complicated environment and high interstitial pressure in tumor tissue, they can return to the bloodstream and cause secondary side effects in normal organs. Recently, a number of nanogatekeepers have been engineered via structure-transformable/stable strategies to overcome this undesirable dilemma. The emerging structure-transformable nanogatekeepers for tumor imaging and therapy are first overviewed here, particularly for nanogatekeepers undergoing structural transformation in tumor microenvironments, cell membranes, and organelles. Thereafter, intelligent structure-stable nanogatekeepers through reversible activation and artificial individualization receptors are overviewed. Finally, the ongoing challenges and prospects of nanogatekeepers for clinical translation are briefly discussed.

Hemodynamic and Morphological Parameters of Ruptured Mirror Posterior Communicating Artery Aneurysms.

Objective: Morphological and hemodynamic parameters might predict rupture of intracranial aneurysms (IAs). A practical model for the study is patients with ruptured mirror IAs in which one is ruptured and the other is unruptured. Although there have been analyses of the morphology and hemodynamics of ruptured mirror posterior communicating artery aneurysms (PComAAs), the sample sizes in these studies were small and only considered hemodynamics or morphological characters. Therefore, this study aimed to investigate the morphological and hemodynamic parameters associated with ruptured mirror PComAAs. Methods: We considered 72 patients with ruptured mirror PComAAs using computational fluid dynamics (CFDs). Ruptured mirror PComAAs were divided into ruptured and unruptured groups. Fourteen morphological and eight hemodynamic parameters were calculated and compared. Significant parameters were analyzed by the multivariate logistic regression to identify independent risk factors. Receiver operating characteristic (ROC) analysis was performed, and the area under the ROC curve (AUC) was calculated for all independent risk factors to determine the predictability and identify the optimal threshold. Results: Four hemodynamic and three morphological parameters were significantly different between ruptured and unruptured groups: normalized wall shear stress (NWSS), mean WSS, low wall shear WSS area (LSA%), size, aspect ratio (AR), size ratio (SR), and inflow angle (IA). Multivariate logistic regression analysis showed that AR, SR, NWSS, mean WSS, and LSA% were all independent factors significantly associated with PComAAs rupture. The ROC analysis for independent risk factors indicated that AR (0.751), NWSS (0.755), mean WSS (0.69), and LSA (0.778) had merely acceptable AUC values. Only SR (0.803) had a high acceptable AUC value. The threshold value of SR was 1.96. Conclusions: SR (>1.96) was the most significant parameter associated with IA rupture, whereas AR, NWSS, mean WSS, and LSA independently characterized the status of IA rupture.

Pueraria flavones-loaded bile salt liposomes with improved intestinal absorption and oral bioavailability: in vitro and in vivo evaluation.

Pueraria flavone (PF), the main component of Pueraria lobata, is a traditional Chinese medicine used for the treatment of cardiovascular and cerebrovascular diseases; however, it exhibits low oral bioavailability because of its poor membrane permeability. In this study, PF-loaded sodium deoxycholate-decorated liposomes (SDC-Lips) were prepared using the reverse-phase evaporation method and optimised using the Box-Behnken design method. The morphology, particle size, zeta potential, and entrapment efficiency of these PF-loaded SDC-Lips were evaluated. The release behaviours of PF-loaded SDC-Lips in simulated gastric and intestinal fluids were consistent with the Weibull kinetic model. In situ intestinal perfusion studies showed that the absorption characteristics of free PF in rats were mainly passive diffusion and partly active transport, and the duodenum was the main absorption site. After encapsulated with SDC-Lips, the absorption of PF increased significantly. The in vivo pharmacokinetic parameters of area under the plasma concentration-time curve (AUC)(0 → 12 h) and AUC(0 → ∞) of PF-loaded SDC-Lips after intragastric administration were 1.34-fold and 1.543-fold, respectively. Overall, the PF-loaded SDC-Lips improved the oral absorption of PF by increasing its solubility and might be considered a promising formulation strategy for prolonging the biological activity time of PF.

A Modified Treatment Through Point-to-Point Coil Embolization for Direct Carotid Cavernous to Fistula: A Single-Center Result.

This study aims to assess the safety and efficacy of the modified treatment through point-to-point coil embolization of direct carotid cavernous fistula (dCCF), and evaluate the long-term outcome of patients who underwent the above treatment. A total of 18 patients who suffered from dCCF (a total of 19 fistulas) between January 2013 to May 2020 were analyzed. Among these patients, 14 patients were treated through point-to-point coil embolization of the fistula, while four patients were treated through combined endovascular embolization (coils, a balloon, Onyx, and/or a stent). The number of coils that filled the fistulas was counted. The primary outcome was defined by post-operative digital subtraction angiography (DSA) or the signs after the recanalization of dCCFs during the follow-up period. For patients with dCCF who underwent point-to-point coil embolization, a minimum of three coils and a maximum of 16 coils were used for these 14 fistula patients, and an average of 7.9 coils were used for each fistula, but none of the fistulas was recanalized. Furthermore, two pseudoaneurysms were observed as a result of the compression of the coils. However, none of these 14 patients presented with signs of recanalization of fistulas or cranial paralysis. The procedure applied for the present study was shown to be a safe, economical and efficacious treatment approach for dCCFs through the point-to-point coil embolization of the fistula.

Interleukin-6 in Cerebrospinal Fluid Small Extracellular Vesicles as a Potential Biomarker for Prognosis of Aneurysmal Subarachnoid Haemorrhage.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) is a severe form of stroke characterized by high rates of mortality and disability. Identifying circulating biomarkers is helpful to improve outcomes. In this study, for the first time, we identify interleukin-6 (IL-6) in cerebrospinal fluid (CSF) small extracellular vesicles (sEVs) as potential biomarkers for prognosis of aSAH. METHODS: We extracted small extracellular vesicles from the CSF of 103 aSAH patients and 40 healthy controls in a prospective observational study. Subsequently, we measured IL-6sEVs levels using an enzyme-linked immunosorbent assay. Results were statistically analyzed to determine the function of IL-6sEVs for disease monitoring of aSAH. RESULTS: CSF IL-6 sEVs showed distinct pattern differences between healthy controls and aSAH patients. The concentration of IL-6sEVs in CSF is significantly correlated with the severity of aSAH patients. The areas under the receiver operating characteristic curves of IL-6sEVs for identifying severe aSAH patient from aSAH patients were 0.900. After multivariate logistic regression analysis, IL-6sEVs were associated with neurological outcome at 1 year. IL-6sEVs levels were greater and positively associated with disease processes and outcome. CONCLUSION: There is a neuroinflammatory cascade in aSAH patients. IL-6sEVs in CSF may be a biomarker for the progression of aSAH.

Paeonol-loaded PLGA nanoparticles as an oral drug delivery system: Design, optimization and evaluation.

Herein, we report a novel type of NPs by loading paeonol (Pae) into PLGA NPs, to enhance drug stability and oral bioavailability. The paeonol (Pae)-loaded polylactic-co-Gly-colic acid (PLGA) nanoparticles (Pae-PLGA-NPs) were prepared by nanoprecipitation method. The resultant NPs were in spherical shape with an average particle size around 237.7 ± 4.92 nm, and the PDI and zeta potential were 0.110 ± 0.01 and -25.33 ± 1.37 mV, respectively. The encapsulation efficiency (EE) and drug loading (DL) of the Pae-PLGA-NPs were 86.26 ± 1.12 and 12.74 ± 0.37% respectively. The in vitro drug release, in vivo pharmacokinetics and in situ single-pass intestinal perfusion (SPIPs) of Pae-PLGA-NPs was investigated. In vivo, the AUC(0-t), C max, MRT(0-t), and T1/2z of the Pae-PLGA-NPs group were 3.79-, 1.89-, 1.40- and 1.49-fold greater than those of the Pae suspension group, respectively. The in situ single-pass intestinal perfusion of NPs results showed the Ka values in the duodenum, jejunum, ileum and colon were 1.12-, 1.40-, 1.52- and 2.21-fold higher than those of Pae solution, respectively. Moreover, the Papp values of the ileum and colon were 1.27- and 1.31-fold higher than those of the solution group. Such findings suggested the Pae-PLGA-NPs can significantly improve the intestinal absorption characteristics, and have a beneficial effect on oral administration as a nanometer-sized carrier.

A Hydraulic Pump Fault Diagnosis Method Based on the Modified Ensemble Empirical Mode Decomposition and Wavelet Kernel Extreme Learning Machine Methods.

To address the problem that the faults in axial piston pumps are complex and difficult to effectively diagnose, an integrated hydraulic pump fault diagnosis method based on the modified ensemble empirical mode decomposition (MEEMD), autoregressive (AR) spectrum energy, and wavelet kernel extreme learning machine (WKELM) methods is presented in this paper. First, the non-linear and non-stationary hydraulic pump vibration signals are decomposed into several intrinsic mode function (IMF) components by the MEEMD method. Next, AR spectrum analysis is performed for each IMF component, in order to extract the AR spectrum energy of each component as fault characteristics. Then, a hydraulic pump fault diagnosis model based on WKELM is built, in order to extract the features and diagnose faults of hydraulic pump vibration signals, for which the recognition accuracy reached 100%. Finally, the fault diagnosis effect of the hydraulic pump fault diagnosis method proposed in this paper is compared with BP neural network, support vector machine (SVM), and extreme learning machine (ELM) methods. The hydraulic pump fault diagnosis method presented in this paper can diagnose faults of single slipper wear, single slipper loosing and center spring wear type with 100% accuracy, and the fault diagnosis time is only 0.002 s. The results demonstrate that the integrated hydraulic pump fault diagnosis method based on MEEMD, AR spectrum, and WKELM methods has higher fault recognition accuracy and faster speed than existing alternatives.

Emerging nanotaxanes for cancer therapy.

The clinical application of taxane (including paclitaxel, docetaxel, and cabazitaxel)-based formulations is significantly impeded by their off-target distribution, unsatisfactory release, and acquired resistance/metastasis. Recent decades have witnessed a dramatic progress in the development of high-efficiency, low-toxicity nanotaxanes via the use of novel biomaterials and nanoparticulate drug delivery systems (nano-DDSs). Thus, in this review, the achievements of nanotaxanes-targeted delivery and stimuli-responsive nano-DDSs-in preclinical or clinical trials have been outlined. Then, emerging nanotherapeutics against tumor resistance and metastasis have been overviewed, with a particular emphasis on synergistic therapy strategies (e.g., combination with surgery, chemotherapy, radiotherapy, biotherapy, immunotherapy, gas therapy, phototherapy, and multitherapy). Finally, the latest oral nanotaxanes have been briefly discussed.

Effect of Micronization on Panax notoginseng: In Vitro Dissolution and In Vivo Bioavailability Evaluations.

Panax notoginseng (PN) has become the most widely used dietary supplement and herbal in Asian countries. The effect of micronization on PN is not entirely clear. The aim of this study was to investigate the effects of particle size of Panax notoginseng powder (PNP) and the potential to improve the bioavailability. The results showed that particle size reduction significantly changed the Panax notoginseng saponins (PNS) in vitro dissolution and in vivo pharmacokinetics. The size of the Panax notoginseng powder (PNP) ranges from 60 to 214 µm. The surface morphology and thermal properties of PNP were extensively characterized, and these changes in physicochemical properties of PNP provide a better understanding of the in vitro and in vivo release behaviors of PNS. The in vitro studies demonstrated that the dissolution of PNS and particle size were nonlinear (dose- and size-dependent). The pharmacokinetics parameters of PNP in rats were determined by UHPLC-MS/MS. Powder 4 (90.38 ± 8.28 µm) showed significantly higher AUC0-T values in plasma (P < 0.05). In addition, we also investigated the influence of the hydrothermal treatment of PNP. The results showed that the PNS in vitro release and in vivo bioavailability of PNP pretreatment at 40°C were the highest. This suggests that PNP with a particle size of around 90 µm and heat pretreatment at 40°C would be beneficial. These results provided an experimental basis, and it was beneficial to choose an appropriate particle size and hydrothermal temperature when PNP was used in clinical treatment.