LAMC1 attenuates neuronal apoptosis via FAK/PI3K/AKT signaling pathway after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The poor prognosis in patients with subarachnoid hemorrhage (SAH) is often attributed to neuronal apoptosis. Recent evidence suggests that Laminin subunit gamma 1 (LAMC1) is essential for cell survival and proliferation. However, the effects of LAMC1 on early brain injury after SAH and the underlying mechanisms are unknown. The current study aimed to reveal the anti-neuronal apoptotic effect and the potential mechanism of LAMC1 in the rat and in the in vitro SAH models. METHODS: The SAH model of Sprague-Dawley rats was established by endovascular perforation. Recombinant LAMC1 (rLAMC1) was administered intranasally 30 min after modeling. LAMC1 small interfering RNA (LAMC1 siRNA), focal adhesion kinase (FAK)-specific inhibitor Y15 and PI3K-specific inhibitor LY294002 were administered before SAH modeling to explore the neuroprotection mechanism of rLAMC1. HT22 cells were cultured and stimulated by oxyhemoglobin to establish an in vitro model of SAH. Subsequently, SAH grades, neurobehavioral tests, brain water content, blood-brain barrier permeability, western blotting, immunofluorescence, TUNEL, and Fluoro-Jade C staining were performed. RESULTS: The expression of endogenous LAMC1 was markedly decreased after SAH, both in vitro and in vivo. rLAMC1 significantly reduced the brain water content and blood-brain barrier permeability, improved short- and long-term neurobehavior, and decreased neuronal apoptosis. Furthermore, rLAMC1 treatment significantly increased the expression of p-FAK, p-PI3K, p-AKT, Bcl-XL, and Bcl-2 and decreased the expression of Bax and cleaved caspase -3. Conversely, knockdown of endogenous LAMC1 aggravated the neurological impairment, suppressed the expression of Bcl-XL and Bcl-2, and upregulated the expression of Bax and cleaved caspase-3. Additionally, the administration of Y15 and LY294002 abolished the protective roles of rLAMC1. In vitro, rLAMC1 significantly reduced neuronal apoptosis, and the protective effects were also abolished by Y15 and LY294002. CONCLUSION: Exogenous LAMC1 treatment improved neurological deficits after SAH in rats, and attenuated neuronal apoptosis in both in vitro and in vivo SAH models, at least partially through the FAK/PI3K/AKT pathway.

Niobium Modification of CeO2 Tuning Electron Density of Nickel-Ceria Interfacial Sites for Enhanced CO2 Methanation.

CO2 methanation has attracted considerable attention as a promising strategy for recycling CO2 and generating valuable methane. This study presents a niobium-doped CeO2-supported Ni catalyst (Ni/NbCe), which demonstrates remarkable performance in terms of CO2 conversion and CH4 selectivity, even when operating at a low temperature of 250 °C. Structural analysis reveals the incorporation of Nb species into the CeO2 lattice, resulting in the formation of a Nb-Ce-O solid solution. Compared with the Ni/CeO2 catalyst, this solid solution demonstrates an improved spatial distribution. To comprehend the impact of the Nb-Ce-O solid solution on refining the electronic properties of the Ni-Ce interfacial sites, facilitating H2 activation, and accelerating the hydrogenation of CO2* into HCOO*, in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) analysis and density functional theory (DFT) calculations were conducted. These investigations shed light on the mechanism through which the activity of CO2 methanation is enhanced, which differs from the commonly observed CO* pathway triggered by oxygen vacancies (OV). Consequently, this study provides a comprehensive understanding of the intricate interplay between the electronic properties of the catalyst's active sites and the reaction pathway in CO2 methanation over Ni-based catalysts.

RU.521 mitigates subarachnoid hemorrhage-induced brain injury via regulating microglial polarization and neuroinflammation mediated by the cGAS/STING/NF-κB pathway.

BACKGROUND: The poor prognosis of subarachnoid hemorrhage (SAH) is often attributed to neuroinflammation. The cGAS-STING axis, a cytoplasmic pathway responsible for detecting dsDNA, plays a significant role in mediating neuroinflammation in neurological diseases. However, the effects of inhibiting cGAS with the selective small molecule inhibitor RU.521 on brain injury and the underlying mechanisms after SAH are still unclear. METHODS: The expression and microglial localization of cGAS following SAH were investigated with western blot analysis and immunofluorescent double-staining, respectively. RU.521 was administered after SAH. 2'3'-cGAMP, a second messenger converted by activated cGAS, was used to activate cGAS-STING. The assessments were carried out by adopting various techniques including neurological function scores, brain water content, blood-brain barrier permeability, western blot analysis, TUNEL staining, Nissl staining, immunofluorescence, morphological analysis, Morris water maze test, Golgi staining, CCK8, flow cytometry in the in vivo and in vitro settings. RESULTS: Following SAH, there was an observed increase in the expression levels of cGAS in rat brain tissue, with peak levels observed at 24 h post-SAH. RU.521 resulted in a reduction of brain water content and blood-brain barrier permeability, leading to an improvement in neurological deficits after SAH. RU.521 had beneficial effects on neuronal apoptosis and microglia activation, as well as improvements in microglial morphology. Additionally, RU.521 prompted a shift in microglial phenotype from M1 to M2. We also noted a decrease in the production of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6, and an increase in the level of the anti-inflammatory cytokine IL-10. Finally, RU.521 treatment was associated with improvements in cognitive function and an increase in the number of dendritic spines in the hippocampus. The therapeutic effects were mediated by the cGAS/STING/NF-κB pathway and were found to be abolished by 2'3'-cGAMP. In vitro, RU.521 significantly reduced apoptosis and neuroinflammation. CONCLUSION: The study showed that SAH leads to neuroinflammation caused by microglial activation, which contributes to early brain injury. RU.521 improved neurological outcomes and reduced neuroinflammation by regulating microglial polarization through the cGAS/STING/NF-κB pathway in early brain injury after SAH. RU.521 may be a promising candidate for the treatment of neuroinflammatory pathology after SAH. Video Abstract.

LVIS-within-enterprise double-stent technique with coil embolization in the treatment of patients with acutely ruptured intracranial vertebrobasilar artery-dissecting aneurysms.

Objective: This study aimed to evaluate the feasibility of the low-profile visualized intraluminal support (LVIS)-within-enterprise double-stent technique for patients with acutely ruptured intracranial vertebrobasilar artery-dissecting aneurysms (ari-VBDAs). Methods: A total of 30 patients with ari-VBDAs who underwent reconstructive treatment using LVIS-within-enterprise double-stent technique with coil embolization between January 2014 and May 2022 were retrospectively enrolled. Patients' characteristics and clinical and imaging outcomes were reviewed. The functional outcomes were assessed using the modified Rankin scale (mRS). Results: A total of 34 ari-VBDAs were identified, including seven (20.6%) basilar artery aneurysms and 27 (79.4%) vertebral artery aneurysms. All aneurysms were successfully treated in the acute phase. In total, six (20.0%) patients experienced in-hospital serious adverse events, including two deaths (6.7%). The median clinical follow-up time of the remaining 28 patients was 20.0 (IQR, 7.3-40.8) months. The incidences of dependency or death (mRS score of 3-6) at discharge and at the last follow-up were 16.7% and 14.3%, respectively. Aneurysm rebleeding occurred in one (3.3%) patient periprocedurally. In total, three (10.0%) patients had ischemic events, one of which occurred during the periprocedural period and two occurred during follow-up. A total of two patients (6.7%) underwent ventriculoperitoneal shunt. Imaging follow-up was available for 14 patients at the median of 12.0 (IQR, 7.0-12.3) months, with a complete occlusion rate of 93.3% (14/15). In total, one patient experienced parent artery occlusion, and no aneurysm was recanalized. Conclusion: LVIS-within-enterprise double-stent technique with coil embolization for the treatment of patients with ari-VBDAs could be performed with a good safety profile and high technical success rate. The rate of complete aneurysm occlusion during follow-up seemed to be satisfactory.

Recent advances in the theoretical studies on the electrocatalytic CO2 reduction based on single and double atoms.

Excess of carbon dioxide (CO2) in the atmosphere poses a significant threat to the global climate. Therefore, the electrocatalytic carbon dioxide reduction reaction (CO2RR) is important to reduce the burden on the environment and provide possibilities for developing new energy sources. However, highly active and selective catalysts are needed to effectively catalyze product synthesis with high adhesion value. Single-atom catalysts (SACs) and double-atom catalysts (DACs) have attracted much attention in the field of electrocatalysis due to their high activity, strong selectivity, and high atomic utilization. This review summarized the research progress of electrocatalytic CO2RR related to different types of SACs and DACs. The emphasis was laid on the catalytic reaction mechanism of SACs and DACs using the theoretical calculation method. Furthermore, the influences of solvation and electrode potential were studied to simulate the real electrochemical environment to bridge the gap between experiments and computations. Finally, the current challenges and future development prospects were summarized and prospected for CO2RR to lay the foundation for the theoretical research of SACs and DACs in other aspects.

Revealing electrocatalytic CN coupling for urea synthesis with metal-free electrocatalyst.

Urea is ubiquitous in agriculture and industry, but its production consumes a lot of energy. The conversion of nitrogen (N2) and carbon dioxide (CO2) into urea via an electrocatalytic CN coupling reaction under ambient conditions would be a major boon to sustainable development. However, designing a metal - free catalyst with high activity and selectivity for urea remains a major challenge. Herein, by means of density functional theory (DFT) and ab - initio molecular dynamics (AIMD) computations, the B12 cluster doped on nitrogenated graphene (C2N) substrate catalyst (B12@C2N) with superior stability was designed for electrocatalytic urea synthesis starting from the CO2 and N2 through four reaction mechanisms. The nature of the co-adsorption activation of CO2 and N2 on the B12@C2N catalyst was investigated, the electrochemical proton - electron transfer steps and the CN thermochemical coupling led to the synthesis of urea. The study showed that the B12@C2N catalyst exhibited high catalytic activity for urea synthesis with the lowest limiting potential of - 1.01 V following the *HNNH mechanism compared with other mechanisms. The potential - determining step (PDS) is the formation of the *CO+*NH2NH2 species. However, the two - step CN coupling barriers of *NCON species are 0.13 eV and 0.60 eV using AIMD and a "slow - growth" sampling approach in an explicit water molecules model. Calculations also showed that the byproducts of carbon monoxide (CO), methane (CH4), methanol (CH3OH), ammonia (NH3), and hydrogen (H2) can be inhibited on the B12@C2N catalyst. Therefore, the metal - free catalyst not only has a good performance for the hydrogenation of CO2 and N2 promoting the electrochemical reaction, but also facilitates CN thermochemical coupling for urea synthesis. This work provides new insights into the synthesis of urea via the CN coupling reaction on a metal - free electrocatalyst, a process that could contribute to greenhouse gas mitigation to help meet carbon neutrality targets.

Construction adsorption and photocatalytic interfaces between C, O co-doped BN and Pd-Cu alloy nanocrystals for effective conversion of CO2 to CO.

Photocatalytic reduction of carbon dioxide (CO2) into fuels is an auspicious route to alleviate the energy and environmental crisis brought by the continuous depletion of fossil fuels. The CO2 adsorption state on the surface of photocatalytic materials plays a significant role in its efficient conversion. The limited CO2 adsorption capacity of conventional semiconductor materials inhibit their photocatalytic performances. In this work, a bifunctional material for CO2 capture and photocatalytic reduction was fabricated by introducing palladium (Pd)-copper (Cu) alloy nanocrystals onto the surface of carbon, oxygen co-doped boron nitride (BN). The elemental doped BN with abundant ultra-micropores had high CO2 capture ability, and CO2 was adsorbed in the form of bicarbonate on its surface with the presence of water vapor. The Pd/Cu molar ratio had great impact on the grain size of Pd-Cu alloy and their distribution on BN. The CO2 molecules tended to be converted to carbon monoxide (CO) at interfaces of BN and Pd-Cu alloys due to their bidirectional interactions to the adsorbed intermediate species while methane (CH4) evolution might occur on the surface of Pd-Cu alloys. Owing to the uniform distribution of smaller Pd-Cu nanocrystals on BN, more effective interfaces were created in the Pd5Cu1/BN sample and it gave a CO production rate of 7.74 µmolg-1h-1 under simulated solar light irradiation, higher than the other PdCu/BN composites. This work can pave a new way for constructing effective bifunctional photo-catalysts with high selectivity to convert CO2 to CO.

Structure-activity relationship of Cu-based catalysts for the highly efficient CO2 electrochemical reduction reaction.

Electrocatalytic carbon dioxide reduction (CO2RR) is a relatively feasible method to reduce the atmospheric concentration of CO2. Although a series of metal-based catalysts have gained interest for CO2RR, understanding the structure-activity relationship for Cu-based catalysts remains a great challenge. Herein, three Cu-based catalysts with different sizes and compositions (Cu@CNTs, Cu4@CNTs, and CuNi3@CNTs) were designed to explore this relationship by density functional theory (DFT). The calculation results show a higher degree of CO2 molecule activation on CuNi3@CNTs compared to that on Cu@CNTs and Cu4@CNTs. The methane (CH4) molecule is produced on both Cu@CNTs and CuNi3@CNTs, while carbon monoxide (CO) is synthesized on Cu4@CNTs. The Cu@CNTs showed higher activity for CH4 production with a low overpotential value of 0.36 V compared to CuNi3@CNTs (0.60 V), with *CHO formation considered the potential-determining step (PDS). The overpotential value was only 0.02 V for *CO formation on the Cu4@CNTs, and *COOH formation was the PDS. The limiting potential difference analysis with the hydrogen evolution reaction (HER) indicated that the Cu@CNTs exhibited the highest selectivity of CH4 among the three catalysts. Therefore, the sizes and compositions of Cu-based catalysts greatly influence CO2RR activity and selectivity. This study provides an innovative insight into the theoretical explanation of the origin of the size and composition effects to inform the design of highly efficient electrocatalysts.

Regulation of the Coordination Structures of Transition Metals on Nitrogen-Doped Carbon Nanotubes for Electrochemical CO2 Reduction.

The electrochemical carbon dioxide reduction reaction (CO2RR) has been extensively studied due to its potential to reduce the globally accelerating CO2 emission and produce value-added chemicals and fuels. Despite great efforts to optimize the catalyst activity and selectivity, the development of robust design criteria for screening the catalysts and understanding the role of water and potassium for CO2 activation poses a significant challenge. Herein, a rapid method for screening single-atom catalysts (SACs) possessing different coordination structures toward the CO2RR process to form CO, namely, a metal atom supported on nitrogen-doped carbon nanotubes (M@CNT, M@1N_CNT, M@2N_CNT, and M@3N_CNT), was established using large-scale density functional theory computations. Adopting the free energy of *CO2 and *OH as screening descriptors, Fe@CNT, Cu@1N_CNT, Pd@2N_CNT, and Ni@3N_CNT were found to exhibit high activity for CO in the gas phase with the overpotential values of 0.22, 0.11, 0.13, and 0.05 V, respectively. Water and potassium present on the surface of the active sites can accelerate the activation of CO2 relative to the gas phase. Ni@3N_CNT shows the highest activity and selectivity in the environment having four water and one potassium. Particularly, the least absolute shrinkage and selection operator regression study revealed that the CO2 adsorption is intrinsically governed by the number of electrons lost by the metal atom in the three N-doped systems, which can be correlated to the distance of the metal atom from the plane of the coordination atom in the M@CNT system. Besides, the study proposes equations for the calculation of the free energy of CO2 adsorption. The current work not only advances the exploration of highly active SACs for the heterogeneous electrocatalytic systems for CO2RR but also highlights the significance of water and potassium in the aqueous solution.

Network pharmacological prediction and molecular docking analysis of the combination of Atractylodes macrocephala Koidz. and Paeonia lactiflora Pall. in the treatment of functional constipation and its verification.

BACKGROUND: We aimed to reveal the mechanism of functional constipation in the treatment of Atractylodes macrocephala Koidz. (AMK) and Paeonia lactiflora Pall. (PLP). METHODS: The main active ingredients of AMK and PLP were screened by the Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform. A database of functional constipation targets was established by GeneCard and OMIM. An "ingredient-target" network map was constructed with Cytoscape software (version 3.7.1), and molecular docking analysis was performed on the components and genes with the highest scores. The rats in the normal group were given saline, and those in the other groups were given 10 mg/kg diphenoxylate once a day for 14 days. The serum and intestinal tissue levels of adenosine monophosphate (cAMP), protein kinase A (PKA), and adenylyl cyclase (AC) of the rats and aquaporin (AQP)1, AQP3, and AQP8 were measured. RESULTS: AMK and PLP had a significant role in the regulation of targets in the treatment of functional constipation. After treatment with AMK, PLP, or mosapride, the serum and intestinal tissue levels of AC, cAMP, and PKA were significantly downregulated. Groups receiving AMK and PLP or mosapride exhibited a reduction in the level of AQP1, AQP3, and AQP8 to varying degrees. CONCLUSION: Molecular docking analysis revealed that AMK and PLP had a significant role in the regulation of targets in the treatment of functional constipation. Studies have confirmed that AMK and PLP can also affect AC, cAMP, and PKA. AC, cAMP, and PKA in model rats were significantly downregulated. AQP expression is closely related to AC, cAMP, and PKA. AMK and PLP can reduce the expression of AQP1, AQP3, and AQP9 in the colon of constipated rats.

Endovascular Management of Vertebrobasilar Trunk Artery Large Aneurysms: Complications and Long-Term Results.

OBJECTIVE: To analyze the complications and long-term results of endovascular management of vertebrobasilar trunk large (≥10 mm) aneurysms (VBTLAs) and identify predictors of outcomes. METHODS: Between 2014 and 2020, 6,987 patients with intracranial aneurysms were referred to our center for aneurysm management and 2,224 patients have undergone the endovascular procedures. We retrospectively reviewed the database and identify all the patients with VBTLAs. RESULTS: A total of 62 VBTLAs were identified. The median aneurysm size was 13.4 mm [interquartile range (IQR) 11.5-18.7]. Among them, 24 aneurysms were treated with overlapping stent techniques, 18 aneurysms were treated with flow diversion, 14 aneurysms were treated with single stent-assisted coiling, and 6 aneurysms were treated with coiling alone. Ten patients were treated with parent artery occlusion or unilateral vertebral artery occlusion. Periprocedural complications were occurred in 7 (11.3%) patients. Clinical follow-up was obtained at the median of 27.5 months (IQR 15.3-58.5). The overall complication rate was 16.1% (10/62), including nine ischemic events and one hemorrhagic event. The combined disability and neurological mortality rate was 12.9% (8/62), with 4 (6.5%) deaths. The favorable outcome rate at follow-up was 87.1% (54/62). The complication-free cumulative survival rates at 1 and 5 years were 86.8 and 82.0%, respectively. The overall cumulative survival rates at 1 and 5 year were 96.5 and 89.8%, respectively. In the multivariate Cox regression analysis, longer procedure time (>115 min) (P = 0.037) and ischemic onset (P = 0.005) predict complications. Angiography follow-up was available for 36 patients at the median of 6.0 months (IQR 6-12), with a complete occlusion rate of 77.8% (28/36). Two (5.6%) aneurysms were recanalized and subsequently received the retreatment. Subgroup analysis did not find any differences in the complete occlusion rate between endovascular strategies. CONCLUSION: Endovascular management of VBTLAs has a reasonable safety profile with favorable 5-year cumulative survival rates and imaging outcomes at follow-up. Prolonged procedure and ischemic onset are associated with a high risk of overall complications.

Effect of nickel-based electrocatalyst size on electrochemical carbon dioxide reduction: A density functional theory study.

The electrochemical carbon dioxide (CO2) reduction reaction (CO2RR) used for converting higher-value chemicals is a promising solution to mitigate CO2 emissions. Nickel (Ni)-based catalysts have been identified as a potential candidate for CO2 activation and conversion. However, in the CO2RR, the size effect of the Ni-based electrocatalysts has not been well explored. Herein, the single Ni atom and the Ni4 cluster doped nitrogen-doped carbon nanotube (Ni@CNT and Ni4@CNT), and the Ni (110) facet were designed to explore the size effect in the CO2RR by using density functional theory (DFT) calculations. The results show that carbon monoxide (CO) is produced on the Ni@CNT with a free energy barrier of 0.51 eV. The reduction product of CO2 on the Ni4@CNT and Ni(110) facet is methane (CH4) in both cases, via different reaction pathways, and the Ni(110) facet is a more efficient electrocatalyst with a low overpotential of 0.27 V when compared to Ni4@CNT (0.50 V). The rate-determining step (RDS) is the formation of *CHO on the Ni4@CNT (The "*" represents the catalytic surface), while the *COH formation is the RDS on the Ni(110) facet. Meanwhile, the Ni(110) facet also has the highest selectivity of CH4 among the three catalysts. The CO2 reduction product changes from CO to CH4 with the increasing size of the Ni-based catalysts. These results demonstrate that the catalytic activity and selectivity of CO2RR highly depend on the size of the Ni-based catalysts.

Time correlation of success recanalization for endovascular recanalization of medically refractory non-acute intracranial arterial occlusions.

Background and purpose: The management of patients with symptomatic non-acute atherosclerotic intracranial artery occlusion (sNAA-ICAO), which is a special subset with high morbidity and a high probability of recurrent serious ischemic events despite standard medical therapy, has been clinically challenging. A number of small-sample clinical studies have discussed endovascular recanalization for sNAA-ICAO and the lack of a uniform standard of operation time. The purpose of this study was to investigate the time correlation of successful recanalization. Methods: From January 2013 to August 2021, 69 consecutive patients who underwent endovascular recanalization for sNAA-ICAO were analyzed retrospectively in the First Affiliated Hospital of Harbin Medical University. The technical success rate, periprocedural complications, and rate of TIA/ischemic stroke during follow-up were evaluated. Results: The overall technical success rate was 73.91% (51/69), and the rate of perioperative complications was 37.68% (26/69). The percentage of patients with perioperative symptoms was 27.53% (19/69). The rate of serious symptomatic perioperative complications was 8.70% (6/69). After adjusting for age, sex, and BMI, the effect of the time from the last symptom to operation on successful recanalization was 0.42 (IQR, 0.20, 0.88, P = 0.021), before the inflection point (51 days). Conclusions: Endovascular recanalization for sNAA-ICAO is technically feasible in reasonably selected patients. The perioperative safety is within the acceptable range. Before 51 days, the last symptoms to operation time, for every 10 days of delay, the probability of successful recanalization is reduced by 57%.

Network-based pharmacology to predict the mechanism of Ginger and Forsythia combined treatment of viral pneumonia.

BACKGROUND: Viral pneumonia (VP) is a common inflammatory disease caused by a virus in the upper respiratory tract. However, current treatment options for pneumonia are limited because of the strong infectivity and lack of research. METHOD: Based on various databases, the mechanisms of Ginger and Forsythia were predicted by network pharmacology. The possible active ingredients of Ginger and Forsythia were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and screened by pharmacokinetic parameters. Their possible targets were predicted by the TCMSP database. The VP-related targets were collected from the GeneCards and OMIM databases. The compound-target-disease network was visualized by Cytoscape 3.7.1. In addition, the protein functional annotation and identification of signalling pathways of possible targets were performed with Gene Ontology (GO) and KEGG enrichment analysis. Molecular docking was finally employed for in silico simulation matching between representative Ginger and Forsythia compounds and their core genes. RESULTS: Twenty-eight active ingredients of Ginger and Forsythia were found and 30 common targets for the combined treatment of VP were obtained. The enrichment analysis of GO functions and KEGG pathways included 186 GO function entries and 56 KEGG pathways. Molecular docking showed that the main ingredients can closely bind three targets (CASP3, JUN, and ESR1). Thus, Ginger and Forsythia play significant roles in the prevention and treatment of VP, and this study showed their mechanism was "multicomponent, multitarget, and multipathway" for the prevention and treatment of VP. CONCLUSION: We successfully predicted the active components and targets of Ginger and Forsythia for prevention and treatment of VP. This may systematically clarify its mechanism of action and provide a direction for future research.