Cellular Heterogeneity of Activated Primary Human Macrophages and Associated Drug-Gene Networks: From Biology to Precision Therapeutics.

BACKGROUND: Interferon-γ (IFNγ) signaling plays a complex role in atherogenesis. IFNγ stimulation of macrophages permits in vitro exploration of proinflammatory mechanisms and the development of novel immune therapies. We hypothesized that the study of macrophage subpopulations could lead to anti-inflammatory interventions. METHODS: Primary human macrophages activated by IFNγ (M(IFNγ)) underwent analyses by single-cell RNA sequencing, time-course cell-cluster proteomics, metabolite consumption, immunoassays, and functional tests (phagocytic, efferocytotic, and chemotactic). RNA-sequencing data were analyzed in LINCS (Library of Integrated Network-Based Cellular Signatures) to identify compounds targeting M(IFNγ) subpopulations. The effect of compound BI-2536 was tested in human macrophages in vitro and in a murine model of atherosclerosis. RESULTS: Single-cell RNA sequencing identified 2 major clusters in M(IFNγ): inflammatory (M(IFNγ)i) and phagocytic (M(IFNγ)p). M(IFNγ)i had elevated expression of inflammatory chemokines and higher amino acid consumption compared with M(IFNγ)p. M(IFNγ)p were more phagocytotic and chemotactic with higher Krebs cycle activity and less glycolysis than M(IFNγ)i. Human carotid atherosclerotic plaques contained 2 such macrophage clusters. Bioinformatic LINCS analysis using our RNA-sequencing data identified BI-2536 as a potential compound to decrease the M(IFNγ)i subpopulation. BI-2536 in vitro decreased inflammatory chemokine expression and secretion in M(IFNγ) by shrinking the M(IFNγ)i subpopulation while expanding the M(IFNγ)p subpopulation. BI-2536 in vivo shifted the phenotype of macrophages, modulated inflammation, and decreased atherosclerosis and calcification. CONCLUSIONS: We characterized 2 clusters of macrophages in atherosclerosis and combined our cellular data with a cell-signature drug library to identify a novel compound that targets a subset of macrophages in atherosclerosis. Our approach is a precision medicine strategy to identify new drugs that target atherosclerosis and other inflammatory diseases.

A novel classification that defines the normal cervical spine: an analysis based on 632 asymptomatic Chinese volunteers.

PURPOSE: The "normal" cervical spine may be non-lordotic shapes and the cervical spine alignment targets are less well established. So, the study was to propose novel classification for cervical spine morphologies with Chinese asymptomatic subjects, and to address cervical balance status based on the classification. METHOD: An overall 632 asymptomatic individuals on cervical spine were selected from January 2020 to December 2022, with six age groups from 20-30 year to 70 plus group. Cervical alignment contained C2-7 cervical lordosis (C2-7 CL) and T1 slope (T1S), together with C1-2 CL, C2-4 CL, C5-7 CL, C2S, cervical sagittal vertical axis (CSVA), thoracic inlet angle (TIA) and neck tilt (NT). C2-7 cervical lordosis was regarded as primary outcomes. To identify groups with similar cervical alignment parameters, a 2-step cluster analysis was performed. RESULTS: C2-7 CL, T1S, CSVA, TIA and NT increased by age and mean value of them were larger in male than female group. Four unique clusters of female lordotic cluster, female kyphotic cluster, male lordotic cluster and male kyphotic cluster were classified mainly based on gender and C2-C7 CL. T1S was the independent influencing factor for C2-7 CL in all individuals and C2-7 CL = -28.65 + 0.57 × TIA, which varied from clusters. Although interactions among cervical parameters, it showed the alignment was more coordinated in lordotic groups. CONCLUSIONS: The cervical sagittal profile varied with age and gender. Four clusters were naturally classified based on C2-7 CL and gender. The cervical balance status was addressed by C2-7 CL = - 28.65 + 0.57 × TIA.

Associations of maternal pre-pregnancy BMI and gestational weight gain with the risks of adverse pregnancy outcomes in Chinese women with gestational diabetes mellitus.

BACKGROUND: Give the high background risk of adverse pregnancy outcomes (APOs), it is important to understand the associations of maternal pre-pregnancy body mass index (ppBMI), gestational weight gain (GWG) with APOs in women with gestational diabetes mellitus (GDM). We addressed the independent and joint associations of maternal ppBMI and GWG with APOs in Chinese women with GDM. METHODS: 764 GDM women with singleton delivery were studied and they were stratified into three weight groups by ppBMI (underweight, normal weight and overweight/obesity) following classification standards for Chinese adults and three GWG groups (inadequate, adequate, excessive GWG) by the 2009 Institute of Medicine guidelines, respectively. Univariate and multivariate logistic regression analyses were performed to estimate the odds ratios of APOs. RESULTS: Maternal overweight/obesity was associated with increased odds of pregnancy-induced hypertension [PIH, adjusted odds ratio (aOR): 2.828, 95% confidence interval (CI) 1.382-5.787], cesarean delivery (CS) (aOR 2.466, 95%CI 1.694-3.590), preterm delivery (aOR 2.466, 95%CI 1.233-4.854), LGA (aOR 1.664, 95%CI 1.120-2.472), macrosomia (aOR 2.682, 95%CI 1.511-4.760) and any pregnancy complication (aOR 2.766, 95%CI 1.840-4.158) compared with healthy weight. Inadequate GWG was less likely to develop PIH (aOR 0.215, 95%CI 0.055-0.835), CS (aOR 0.612, 95%CI 0.421-0.889) and any pregnancy complication (aOR 0.628, 95%CI 0.435-0.907), but had higher risk of preterm birth (aOR 2.261, 95%CI 1.089-4.692), while excessive GWG was more vulnerable to LGA (aOR 1.929, 95%CI 1.272-2.923), macrosomia (aOR 2.753, 95%CI 1.519-4.989) and any pregnancy complication (aOR 1.548, 95%CI 1.006-2.382) as compared to adequate GWG. Furthermore, compared to normal weight mothers with adequate GWG, obese mothers with excessive GWG had the highest risk of any pregnancy complication (aOR 3.064, 95%CI 1.636-5.739). CONCLUSIONS: Maternal overweight/obesity and GWG were associated with APOs in the already high-risk settings of GDM. Obese mothers with excessive GWG may confer the greatest risk of adverse outcomes. It was very helpful to reduce the burden of APOs and benefit GDM women by promoting a healthy pre-pregnancy BMI and GWG.

Synthesis of Two-Dimensional Covalent Organic Frameworks in Ionic Liquids.

Two-dimensional covalent organic frameworks were synthesized in high yields by polycondensation in nonvolatile ionic liquids. The resulting crystallites are highly porous and exhibit exceptional capability of removing bisphenol A from water. The one reported is a general method to synthesize microporous and mesoporous frameworks, it allows to achieve regular macroscopic shapes, and it is effective in a wide range of reaction temperatures.

A 3D Covalent Organic Framework with Exceptionally High Iodine Capture Capability.

Using porous materials to cope with environmental issues is promising but remains a challenge especially for removing the radioactive vapor wastes in fission because of harsh adsorption conditions. Here we report a new, stable covalent organic framework (COF) as a porous platform for removing iodine vapor-a major radioactive fission waste. The three-dimensional COF consists of a diamond topology knotted by adamantane units, creates ordered one-dimensional pores and are highly porous. The COF enables the removal of iodine vapor via charge transfer complex formation with the pore walls to achieve exceptional capacity. Moreover, the 3D COF is "soft" to trigger structural fitting to iodine while retaining connectivity and enables cycle use for many times while retaining high uptake capacity. These results set a new benchmark for fission waste removal and suggest the great potential of COFs as a designable porous material for challenging world-threatening pollution issues.

Sophisticated Design of Covalent Organic Frameworks with Controllable Bimetallic Docking for a Cascade Reaction.

Precise control of the number and position of the catalytic metal ions in heterogeneous catalysts remains a big challenge. Here we synthesized a series of two-dimensional (2D) covalent organic frameworks (COFs) containing two different types of nitrogen ligands, namely imine and bipyridine, with controllable contents. For the first time, the selective coordination of the two nitrogen ligands of the 2D COFs to two different metal complexes, chloro(1,5-cyclooctadiene)rhodium(I) (Rh(COD)Cl) and palladium(II) acetate (Pd(OAc)2 ), has been realized using a programmed synthetic procedure. The bimetallically docked COFs showed excellent catalytic activity in a one-pot addition-oxidation cascade reaction. The high surface area, controllable metal-loading content, and predesigned active sites make them ideal candidates for their use as heterogeneous catalysts in a wide range of chemical reactions.

The pharmacology of cyclopropyl-methoxycarbonyl metomidate: a comparison with propofol.

BACKGROUND: Cyclopropyl-methoxycarbonyl metomidate (CPMM) is a "soft" etomidate analogue currently being developed as a propofol alternative for anesthetic induction and maintenance. METHODS: We compared the potencies of CPMM and propofol by assessing their abilities to directly activate α1(L264T)ß3γ2 gamma-aminobutyric acid type A (GABAA) receptors and induce loss of righting reflexes in tadpoles. We also measured the rates of encephalographic recovery in rats after CPMM and propofol infusions ranging in duration from 5 to 120 minutes. RESULTS: CPMM and propofol activate GABAA receptors and induce loss of righting reflexes in tadpoles with respective 50% effective concentrations (EC50s) of 3.8 ± 0.4 and 3.9 ± 0.2 µM (GABAA receptor) and 2.6 ± 0.19 and 1.3 ± 0.04 µM (tadpole). Encephalographic recovery after prolonged infusion was faster with CPMM and lacked propofol's context sensitivity. CONCLUSION: CPMM and propofol have similar potencies in GABAA receptors and tadpoles; however, CPMM provides more rapid and predictable recovery than propofol, particularly after prolonged infusion.

Capacitive-Controlled Prussian White with a Nickel Iron Hexacyanoferrate Composite Cathode for Rapid Sodium Diffusion.

Prussian blue analogues receive tremendous attention owing to their spacious three-dimensional skeleton, high theoretical specific capacity, facile synthesis procedure, and high cost-effectiveness as among the most promising candidates for cathode materials in sodium-ion batteries (SIBs). Nonetheless, the practical specific capacity, especially under high current, is particularly frail due to the sluggish ion diffusion. In this study, the strategy of Ni substitution and formation of water-coordinated Fe is applied to lower the crystal field energy and elevate the active low-spin (LS) Fe content, which leads to a capacitive sodium storage mechanism, resulting in a substantial specific capacity under high current density. The delivered specific capacity of PW-325@2NiFe-55 is 95 mAh g-1 at 50 C, which is 72.5% capacity retention of the one at 0.5 C. Also, it maintains 80.2% of its initial specific capacity after 500 cycles at 5 C. Furthermore, a hypothesis of a joint diffusion-controlled and capacitive mechanism for high-spin (HS) Fe and a mere capacitive mechanism for LS Fe is put forward and verified through potentiastatic tests, operando 57Fe Mössbauer spectroscopy, and ex situ XRD, which provides a new horizon to enhance the electrochemical performance for SIBs.

Defect-Engineering-Mediated Long-Lived Charge-Transfer Excited-State in Fe-Gallate Complex Improves Iron Cycle and Enables Sustainable Fenton-Like Reaction.

Fenton reactions are inefficient because the Fe(II) catalyst cannot be recycled in time due to the lack of a rapid electron transport pathway. This results in huge H2 O2 wastage in industrial applications. Here, it is shown that a sustainable heterogeneous Fenton system is attainable by enhancing the ligand-to-metal charge-transfer (LMCT) excited-state lifetime in Fe-gallate complex. By engineering oxygen defects in the complex, the lifetime is improved from 10-90 ps. The lengthened lifetime ensures sufficient concentrations of excited-states for an efficient Fe cycle, realizing previously unattainable H2 O2 activation kinetics and hydroxyl radical (• OH) productivity. Spectroscopic and electrochemical studies show the cyclic reaction mechanism involves in situ Fe(II) regeneration and synchronous supply of oxygen atoms from water to recover dissociated Fe─O bonds. Trace amounts of this catalyst effectively destroy two drug-resistant bacteria even after eight reaction cycles. This work reveals the link among LMCT excited-state lifetime, Fe cycle, and catalytic activity and stability, with implications for de novo design of efficient and sustainable Fenton-like processes.

Highly Active and Sintering-Resistant Pt Clusters Supported on FeOx-Hydroxyapatite Achieved by Tailoring Strong Metal-Support Interactions.

The catalytic performance of supported metal catalysts is closely related to their structure. While Pt-based catalysts are widely used in many catalytic reactions because of their exceptional intrinsic activity, they tend to deactivate in high-temperature reactions, requiring a tedious and expensive regeneration process. The strong metal-support interaction (SMSI) is a promising strategy to improve the stability of supported metal nanoparticles, but often at the price of the activity due to either the coverage of the active sites by support overlay and/or the too-strong metal-support bonding. Herein, we newly constructed a supported Pt cluster catalyst by introducing FeOx into hydroxyapatite (HAP) support to fine-tune the SMSIs. The catalyst exhibited not only high catalytic activity but also sintering resistance, without deactivation in a 100 h test for catalytic CO oxidation. Detailed characterizations reveal that FeOx introduced into HAP weaken the strong covalent metal-support interaction (CMSI) between Pt and FeOx while simultaneously inhibiting the oxidative strong metal-support interaction (OMSI) between Pt and HAP, giving rise to both high activity and thermal stability of the supported Pt clusters.

Astrocyte-derived lactoferrin reduces ß-amyloid burden by promoting the interaction between p38 kinase and PP2A phosphatase in male APP/PS1 transgenic mice.

BACKGROUND AND PURPOSE: Overexpression of astrocytic lactoferrin (Lf) was observed in the brain of Alzheimer's disease (AD) patients, whereas the role of astrocytic Lf in AD progression remains unexplored. In this study, we aimed to evaluate the effects of astrocytic Lf on AD progression. EXPERIMENTAL APPROACH: Male APP/PS1 mice with astrocytes overexpressing human Lf were developed to evaluate the effects of astrocytic Lf on AD progression. N2a-sw cells also were employed to further uncover the mechanism of astrocytic Lf on ß-amyloid (Aß) production. KEY RESULTS: Astrocytic Lf overexpression increased protein phosphatase 2A (PP2A) activity and reduced amyloid precursor protein (APP) phosphorylation, Aß burden and tau hyperphosphorylation in APP/PS1 mice. Mechanistically, astrocytic Lf overexpression promoted the uptake of astrocytic Lf into neurons in APP/PS1 mice, and conditional medium from astrocytes overexpressing Lf inhibited p-APP (Thr668) expression in N2a-sw cells. Furthermore, recombinant human Lf (hLf) significantly enhanced PP2A activity and inhibited p-APP expression, whereas inhibition of p38 or PP2A activities abrogated the hLf-induced p-APP down-regulation in N2a-sw cells. Additionally, hLf promoted the interaction of p38 and PP2A via p38 activation, thereby enhancing PP2A activity, and low-density lipoprotein receptor-related protein 1 (LRP1) knockdown significantly reversed the hLf-induced p38 activation and p-APP down-regulation. CONCLUSIONS AND IMPLICATIONS: Our data suggested that astrocytic Lf promoted neuronal p38 activation, via targeting to LRP1, subsequently promoting p38 binding to PP2A to enhance PP2A enzyme activity, which finally inhibited Aß production via APP dephosphorylation. In conclusion, promoting astrocytic Lf expression may be a potential strategy against AD. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

Adrenocortical suppression and recovery after continuous hypnotic infusion: etomidate versus its soft analogue cyclopropyl-methoxycarbonyl metomidate.

INTRODUCTION: Etomidate is no longer administered as a continuous infusion for anesthetic maintenance or sedation, because it results in profound and persistent suppression of adrenocortical steroid synthesis with potentially lethal consequences in critically ill patients. We hypothesized that rapidly metabolized soft analogues of etomidate could be developed that do not produce persistent adrenocortical dysfunction even after prolonged continuous infusion. We hope that such agents might also provide more rapid and predictable anesthetic emergence. We have developed the soft etomidate analogue cyclopropyl-methoxycarbonyl etomidate (CPMM). Upon termination of 120-minute continuous infusions, hypnotic and encephalographic recoveries occur in four minutes. The aims of this study were to assess adrenocortical function during and following 120-minute continuous infusion of CPMM and to compare the results with those obtained using etomidate. METHODS: Dexamethasone-suppressed rats were randomized into an etomidate group, CPMM group, or control group. Rats in the etomidate and CPMM groups received 120-minute continuous infusions of etomidate and CPMM, respectively. Rats in the control group received neither hypnotic. In the first study, adrenocortical function during hypnotic infusion was assessed by administering adrenocorticotropic hormone (ACTH) 90 minutes after the start of the hypnotic infusion and measuring plasma corticosterone concentrations at the end of the infusion 30 minutes later. In the second study, adrenocortical recovery following hypnotic infusion was assessed by administering ACTH every 30 minutes after infusion termination and measuring plasma corticosterone concentrations 30 minutes after each ACTH dose. RESULTS: During hypnotic infusion, ACTH-stimulated serum corticosterone concentrations were significantly lower in the CPMM and etomidate groups than in the control group (100 ± 64 ng/ml and 33 ± 32 ng/ml versus 615 ± 265 ng/ml, respectively). After hypnotic infusion, ACTH-stimulated serum corticosterone concentrations recovered to control values within 30 minutes in the CPMM group but remained suppressed relative to those in the control group for more than 3 hours in the etomidate group. CONCLUSIONS: Both CPMM and etomidate suppress adrenocortical function during continuous infusion. However, recovery occurs significantly more rapidly following infusion of CPMM.

The effect of water on the microstructure and properties of benzene/[bmim][AOT]/[bmim][BF4] microemulsions.

In the present contribution, results concerning the role of small amounts of water in the 1-butyl-3-methylimidazolium bis 2-ethylhexyl sulfosuccinate ([bmim][AOT]) based 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4])-in-benzene reverse microemulsions are emphasized. The microemulsion aggregates have demonstrated features in common with traditional aqueous systems, such as a normal microemulsion droplet size and decreased stability due to the addition of a polar component. Dynamic light scattering (DLS) showed that the size change of microemulsion with added water depends on the loaded [bmim][BF4] content in the microemulsion: when the [bmim][BF4] content is low, the microemulsion diameter first decreases and then increases, while the size remains about the same for microemulsions with a moderate [bmim][BF4] loading and a successive increase in size was found for high-loaded [bmim][BF4] microemulsions. (1)H NMR along with two-dimensional rotating frame nuclear Overhauser effect (NOE) experiments (ROESY) revealed that water molecules formed wide interactions with both 1-butyl-3-methylimidazolium ([bmim]) and bis 2-ethylhexyl sulfosuccinate ([AOT]), leading to a decrease in the headgroup area of [bmim][AOT], i.e. α value, which will decrease the microemulsion size. On the other hand, addition of water can simultaneously swell the microemulsions, causing an increase in the diameter. It is also deduced that the Coulomb forces between the [AOT] and [bmim] should be one of the main driving forces for the formation of [bmim][BF4]-in-benzene microemulsions.

Carboetomidate: an analog of etomidate that interacts weakly with 11ß-hydroxylase.

BACKGROUND: Carboetomidate is a pyrrole etomidate analog that is 3 orders of magnitude less potent an inhibitor of in vitro cortisol synthesis than etomidate (an imidazole) and does not inhibit in vivo steroid production. Although carboetomidate's reduced functional effect on steroid synthesis is thought to reflect lower binding affinity to 11ß-hydroxylase, differential binding to this enzyme has never been experimentally demonstrated. In the current study, we tested the hypothesis that carboetomidate and etomidate bind with differential affinity to 11ß-hydroxylase by comparing their abilities to inhibit photoaffinity labeling of purified enzyme by a photoactivatable etomidate analog and to modify the enzyme's absorption spectrum in a way that is indicative of ligand binding. In addition, we made a preliminary exploration of the manner in which etomidate and carboetomidate might differentially interact with this site using spectroscopic methods as well as molecular modeling techniques to better understand the structural basis for their selectivity. METHODS: The ability of azi-etomidate to inhibit cortisol synthesis was tested by assessing its ability to inhibit cortisol synthesis by H295R cells. The binding affinities of etomidate and carboetomidate to 11ß-hydroxylase were compared by assessing their abilities to (1) inhibit photoincorporation of the photolabile etomidate analog [(3)H]azi-etomidate into the enzyme and (2) modify the absorption spectrum of the enzyme's heme group. In silico docking studies of etomidate, carboetomidate, and azi-etomidate binding to 11ß-hydroxylase were performed using the computer software GOLD. RESULTS: Similar to etomidate, azi-etomidate potently inhibits in vitro cortisol synthesis. Etomidate inhibited [(3)H]azi-etomidate photolabeling of 11ß-hydroxylase in a concentration-dependent manner. At a concentration of 40 µM, etomidate reduced photoincorporation of [(3)H]azi-etomidate by 96% ± 1% whereas carboetomidate had no experimentally detectable effect. On addition of etomidate to 11ß-hydroxylase, a type 2 difference spectrum was produced indicative of etomidate complexation with the enzyme's heme iron; carboetomidate had no effect whereas azi-etomidate produced a reverse type 1 spectrum. Computer modeling studies predicted that etomidate, carboetomidate, and azi-etomidate can fit into the heme-containing pocket that forms 11ß-hydroxylase's active site and pose with their carbonyl oxygens interacting with the heme iron and their phenyl rings stacking with phenylalanine-80. However, additional unique poses were identified for etomidate and azi-etomidate that likely account for their higher affinities. CONCLUSIONS: Carboetomidate's reduced ability to suppress in vitro and in vivo steroid synthesis as compared with etomidate reflects its lower binding affinity to 11ß-hydroxylase and may be attributed to carboetomidate's inability to form a coordination bond with the heme iron located at the enzyme's active site.

Thoracolumbar/Lumbar Degenerative Kyphosis-The Importance of Thoracolumbar Junction in Sagittal Alignment and Balance.

PURPOSE: To conduct a more comprehensive study of sagittal alignment in patients with thoracolumbar/lumbar (TL/L) degenerative kyphosis. METHODS: A total of 133 consecutive patients from September 2016 to March 2019 with degenerative spinal kyphosis were enrolled. These patients were divided into different types according to sagittal alignment, including thoracolumbar junctional kyphosis (TLJK). Then, we divided the patients with TLJK into two groups: the Sagittal Balance group (C7-SVA < 50 mm) and the Sagittal Imbalance group (C7-SVA ≥ 50 mm). The sagittal parameters of each type or group were compared and correlation analysis was conducted. RESULTS: Thoracolumbar/lumbar degenerative kyphosis consists of four types: Type I, lumbar kyphosis; Type II, degenerative flat back; Type III, thoracolumbar junctional kyphosis; and Type IV, global kyphosis. According to different sagittal alignments, Type III can further be divided into three subtypes: IIIA, with smooth kyphosis of thoracic and upper lumbar; IIIB, like a clasp knife, with a flat thoracic and lumbar angle; and IIIC, with bigger thoracic kyphosis and lumbar lordosis. The thoracolumbar kyphosis angle (°) of the three subtypes were -23.61 ± 5.37, -25.40 ± 7.71, and -40.01 ± 8.40, respectively. Lumbar lordosis was correlated with thoracic kyphosis (IIIA, r = -0.600, p = 0.005; IIIB, r = -0.312, p = 0.046; IIIC, r = -0.657, p = 0.015), and correlated with sacral slope (IIIA, r = 0.537, p = 0.015; IIIB, r = 0.654, p = 0.000; IIIC, r = 0.578, p = 0.039). All spinopelvic parameters were compared between the Sagittal Balance group and the Sagittal Imbalance group, and only the thoracolumbar kyphosis angle showed statistical difference (t = -2.247, p = 0.028). CONCLUSIONS: The common characteristics of thoracolumbar junctional kyphosis were found to be a bigger thoracolumbar junctional angle and vertex of kyphosis located in the thoracolumbar junction (T10-L2). Despite TLJK, a change in the thoracic angle was still important to maintain sagittal balance. The thoracolumbar junction plays an important role in sagittal alignment and balance.

Graphdiyne nanoplatforms for photothermal-ferroptosis combination therapy against glioblastoma.

Glioblastoma (GBM) is one of the most malignant tumors of the central nervous system and has a poor prognosis. GBM cells are highly sensitive to ferroptosis and heat, suggesting thermotherapy-ferroptosis as a new strategy for GBM treatment. With its biocompatibility and photothermal conversion efficiency, graphdiyne (GDY) has become a high-profile nanomaterial. Here, the ferroptosis inducer FIN56 was employed to construct GDY-FIN56-RAP (GFR) polymer self-assembled nanoplatforms against GBM. GDY could effectively load FIN56 and FIN56 released from GFR in a pH-dependent manner. The GFR nanoplatforms possessed the advantages of penetrating the BBB and acidic environment-induced in situ FIN56 release. Moreover, GFR nanoplatforms induced GBM cell ferroptosis by inhibiting GPX4 expression, and 808 nm irradiation reinforced GFR-mediated ferroptosis by elevating the temperature and promoting FIN56 release from GFR. In addition, the GFR nanoplatforms were inclined to locate in tumor tissue, inhibit GBM growth, and prolong lifespan by inducing GPX4-mediated ferroptosis in an orthotopic xenograft mouse model of GBM; meanwhile, 808 nm irradiation further improved these GFR-mediated effects. Hence, GFR may be a potential nanomedicine for cancer therapy, and GFR combined with photothermal therapy may be a promising strategy against GBM.

Ultrastable Fe-N-C Fuel Cell Electrocatalysts by Eliminating Non-Coordinating Nitrogen and Regulating Coordination Structures at High Temperatures.

Pyrolyzed Fe-N-C materials have attracted considerable interest as one of the most active noble-metal-free electrocatalysts for the oxygen reduction reaction (ORR) in proton exchange membrane fuel cells (PEMFCs). Despite significant progress is made in improving their catalytic activity during past decades, the Fe-N-C catalysts still suffer from fairly poor electrochemical and storage stability, which greatly hurdles their practical application. Here, an effective strategy is developed to greatly improve their catalytic stability in PEMFCs and storage stability by virtue of previously unexplored high-temperature synthetic chemistry between 1100 and 1200 °C. Pyrolysis at this rarely adopted temperature range not only enables the elimination of less active nitrogen-doped carbon sites that generate detrimental peroxide byproduct but also regulates the coordination structure of Fe-N-C from less stable D1 (O-FeN4 C12 ) to a more stable D2 structure (FeN4 C10 ). The optimized Fe-N-C catalyst exhibits excellent stability in PEMFCs (>80% performance retention after 30 h under H2 /O2 condition) and no activity loss after 35 day storage while maintaining a competitive ORR activity and PEMFC performance.

Modifying methoxycarbonyl etomidate inter-ester spacer optimizes in vitro metabolic stability and in vivo hypnotic potency and duration of action.

BACKGROUND: Methoxycarbonyl etomidate is the prototypical very rapidly metabolized etomidate analog. Initial studies suggest that it may be too short acting for many clinical uses. We hypothesized that its duration of action could be lengthened and clinical utility broadened by incorporating specific aliphatic groups into the molecule to sterically protect its ester moiety from esterase-catalyzed hydrolysis. To test this hypothesis, we developed a series of methoxycarbonyl etomidate analogs (spacer-linked etomidate esters) containing various aliphatic-protecting groups and spacer lengths. METHODS: Spacer-linked etomidate esters were synthesized and their hypnotic potencies and durations of action following bolus administration were measured in rats using a loss-of-righting reflexes assay. Octanol:water partition coefficients and metabolic half-lives in pooled rat blood were determined chromatographically. RESULTS: All spacer-linked etomidate esters produced hypnosis rapidly and in a dose-dependent manner. ED50s for loss of righting reflexes ranged from 0.69 ± 0.04 mg/kg for cyclopropyl-methoxycarbonyl metomidate to 11.1 ± 0.8 mg/kg for methoxycarbonyl metomidate. The slope of a plot of the duration of loss of righting reflexes versus the logarithm of the dose ranged 12-fold among spacer-linked etomidate esters, implying widely varying brain clearance rates. The in vitro metabolic half-lives of these compounds in rat blood varied by more than two orders of magnitude and were diastereometrically selective. CONCLUSIONS: We created 13 new analogs of methoxycarbonyl etomidate and identified two that have significantly higher potency and potentially address the too-brief duration of action for methoxycarbonyl etomidate. This work may provide a blueprint for optimizing the pharmacological properties of other soft drugs.

Electroencephalographic recovery, hypnotic emergence, and the effects of metabolite after continuous infusions of a rapidly metabolized etomidate analog in rats.

BACKGROUND: Methoxycarbonyl etomidate is an ultrarapidly metabolized etomidate analog. It is metabolized to methoxycarbonyl etomidate carboxylic acid (MOC-ECA), which has a hypnotic potency that is 350-fold less than that of methoxycarbonyl etomidate. The authors explored the relationships between methoxycarbonyl etomidate infusion duration, recovery time, metabolite concentrations in blood and cerebrospinal fluid (CSF), and methoxycarbonyl etomidate metabolism in brain tissue and CSF to test the hypothesis that rapid metabolism of methoxycarbonyl etomidate may lead to sufficient accumulation of MOC-ECA in the brain to produce a pharmacologic effect. METHODS: A closed-loop system with burst suppression ratio feedback was used to administer methoxycarbonyl etomidate infusions of varying durations to rats. After infusion, recovery of the electroencephalogram and righting reflexes were assessed. MOC-ECA concentrations were measured in blood and CSF during and after methoxycarbonyl etomidate infusion, and the in vitro half-life of methoxycarbonyl etomidate was determined in rat brain tissue and CSF. RESULTS: Upon termination of continuous methoxycarbonyl etomidate infusions, the burst suppression ratio recovered in a biexponential manner with fast and slow components having time constants that differed by more than 100-fold and amplitudes that varied inversely with infusion duration. MOC-ECA concentrations reached hypnotic concentrations in the CSF with prolonged methoxycarbonyl etomidate infusion and then decreased during a period of several hours after infusion termination. The metabolic half-life of methoxycarbonyl etomidate in brain tissue and CSF was 11 and 20 min, respectively. CONCLUSION: In rats, methoxycarbonyl etomidate metabolism is sufficiently fast to produce pharmacologically active MOC-ECA concentrations in the brain with prolonged methoxycarbonyl etomidate infusion.

Electroencephalographic and hypnotic recoveries after brief and prolonged infusions of etomidate and optimized soft etomidate analogs.

BACKGROUND: Methoxycarbonyl etomidate is the prototypical soft etomidate analog. Because it has relatively low potency and is extremely rapidly metabolized, large quantities must be infused to maintain hypnosis. Consequently with prolonged infusion, metabolite reaches sufficient concentrations to delay recovery. Dimethyl-methoxycarbonyl metomidate (DMMM) and cyclopropyl-methoxycarbonyl metomidate (CPMM) are methoxycarbonyl etomidate analogs with higher potencies and slower clearance. Because of these properties, we hypothesized that dosing would be lower and electroencephalographic and hypnotic recoveries would be faster - and less context-sensitive - with DMMM or CPMM versus methoxycarbonyl etomidate or etomidate. METHODS: Etomidate, DMMM, and CPMM where infused into rats (n = 6 per group) for either 5 min or 120 min. After infusion termination, electroencephalographic and hypnotic recovery times were measured. The immobilizing ED50 infusion rates were determined using a tail clamp assay. RESULTS: Upon terminating 5-min infusions, electroencephalographic and hypnotic recovery times were not different among hypnotics. However, upon terminating 120-min infusions, recovery times varied significantly with respective values (mean ± SD) 48 ± 13 min and 31 ± 6.5 min (etomidate), 17 ± 7.0 min and 14 ± 3.4 min (DMMM), and 4.5 ± 1.1 min and 4.2 ± 1.6 min (CPMM). The immobilizing ED50 infusion rates were (mean ± SD) 0.19 ± 0.03 mg · kg · min (etomidate), 0.60 ± 0.12 mg · kg · min (DMMM), and 0.89 ± 0.18 mg · kg · min (CPMM). CONCLUSIONS: Electroencephalographic and hypnotic recoveries following prolonged infusions of DMMM and CPMM are faster than those following methoxycarbonyl etomidate or etomidate. In the case of CPMM infusion, recovery times are 4 min and context-insensitive.