Predicting long-term outcomes in patients with classical trigeminal neuralgia following microvascular decompression with an MRI-based radiomics nomogram: a multicentre study.

OBJECTIVES: This study aimed to develop a clinical-radiomics nomogram to predict the long-term outcomes of patients with classical trigeminal neuralgia (CTN) following microvascular decompression (MVD). MATERIALS AND METHODS: This retrospective study included 455 patients with CTN who underwent MVD from three independent institutions A total of 2030 radiomics features from the cistern segment of the trigeminal nerve were extracted computationally from the three-dimensional steady-state free precession and three-dimensional time-of-flight magnetic resonance angiography sequences. Using the least absolute shrinkage and selection operator regression, 16 features were chosen to develop radiomics signatures. A clinical-radiomics nomogram was subsequently developed in the development cohort of 279 patients via multivariate Cox regression. The predictive performance and clinical application of the nomogram were assessed in an external cohort consisting of 176 patients. RESULTS: Sixteen highly outcome-related radiomics features extracted from multisequence images were used to construct the radiomics model, with concordance indices (C-index) of 0.804 and 0.796 in the development and test cohorts, respectively. Additionally, a clinical-radiomics nomogram was developed by incorporating both radiomics features and clinical characteristics (i.e., pain type and degree of neurovascular compression) and yielded higher C-indices of 0.865 and 0.834 in the development and test cohorts, respectively. K‒M survival analysis indicated that the nomogram successfully stratified patients with CTN into high-risk and low-risk groups for poor outcomes (hazard ratio: 37.18, p < 0.001). CONCLUSION: Our study findings indicated that the clinical-radiomics nomogram exhibited promising performance in accurately predicting long-term pain outcomes following MVD. CLINICAL RELEVANCE STATEMENT: This model had the potential to aid clinicians in making well-informed decisions regarding the treatment of patients with CTN. KEY POINTS: Trigeminal neuralgia recurs in about one-third of patients after undergoing MVD. The clinical-radiomics nomogram stratified patients into high- and low-risk groups for poor surgical outcomes. Using this nomogram could better inform patients of recurrence risk and allow for discussion of alternative treatments.

Hybrid Ghost Phonon Polaritons in Thin-Film Heterostructure.

Ghost phonon polaritons (g-PhPs), a unique class of phonon polaritons in the infrared, feature ultralong diffractionless propagation (>20 µm) across the surface and tilted wavefronts in the bulk. Here, we study hybrid g-PhPs in a heterostructure of calcite and an ultrathin film of the phase change material (PCM) In3SbTe2, where the optical field is bound in the PCM film with enhanced confinement compared with conventional g-PhPs. Near-field optical images for hybrid g-PhPs reveal a lemniscate pattern in the momentum distribution. We fabricated In3SbTe2 gratings and investigated how different orientations and periodicities of gratings impact the propagation of hybrid g-PhPs. As the grating period decreases to zero, the wavefront of hybrid g-PhPs can be dynamically steered by varying the grating orientation. Our results highlight the promise of hybrid g-PhPs with tunable functionalities for nanophotonic studies.

Alleviating iatrogenic effects of paclitaxel via antiinflammatory treatment.

BACKGROUND: Paclitaxel (PTX) is touted as an essential medicine due to its extensive use as a chemotherapeutic agent for various cancers and an antiproliferative agent for endovascular applications. Emerging studies in cardio-oncology implicate various vascular complications of chemotherapeutic agents. METHODS: We evaluated the inflammatory response induced by the systemic administration of PTX. The investigation included RNAseq analysis of primary human endothelial cells (ECs) treated with PTX to identify transcriptional changes in pro-inflammatory mediators. Additionally, we used dexamethasone (DEX), a well-known antiinflammatory compound, to assess its effectiveness in counteracting these PTX-induced changes. Further, we studied the effects of PTX on monocyte chemoattractant protein-1 (MCP-1) levels in the media of ECs. The study also extended to in vivo analysis, where a group of mice was injected with PTX and subsequently harvested at different times to assess the immediate and delayed effects of PTX on inflammatory mediators in blood and aortic ECs. RESULTS: Our RNAseq analysis revealed that PTX treatment led to significant transcriptional perturbations in pro-inflammatory mediators such as MCP-1 and CD137 within primary human ECs. These changes were effectively abrogated when DEX was administered. In vitro experiments showed a marked increase in MCP-1 levels in EC media following PTX treatment, which returned to baseline upon treatment with DEX. In vivo, we observed a threefold increase in MCP-1 levels in blood and aortic ECs 12 h post-PTX administration. Similar trends were noted for CD137 and other downstream mediators like tissue factor, vascular cell adhesion molecule 1, and E-selectin in aortic ECs. CONCLUSION: Our findings illustrate that PTX exposure induces an upregulation of atherothrombotic mediators, which can be alleviated with concurrent administration of DEX. Considering these observations, further long-term investigations should focus on understanding the systemic implications associated with PTX-based therapies and explore the clinical relevance of DEX in mitigating such risks.

Protective effect of soluble dietary fiber from Rosa roxburghii Tratt residue on dextran sulfate sodium-induced ulcerative colitis by regulating serum metabolism and NF-κB pathway in mice.

BACKGROUND: Ulcerative colitis (UC) refers to an idiopathic chronic inflammatory bowel disease that starts with inflammation of the intestinal mucosa. Dietary fiber plays a crucial role in maintaining the normal architecture of the intestinal mucosa. In this study, the protective effect and potential mechanism of soluble dietary fiber from Rosa roxburghii Tratt residue (SDFR) on dextran sulfate sodium (DSS)-induced UC mice were explored. RESULTS: The results revealed that SDFR could ameliorate body weight loss and pathological injury, improve the structure and crypt destruction in colon in DSS-induced mice. Moreover, the levels of NO, IL-1ß, TNF-α, MPO and protein expression of iNOS and COX-2 were decreased after administration of SDFR. Notably, nontargeted metabolomics analysis indicated that there were significant differences in 51 potential metabolites in serum between the DSS and control groups. SDFR intervention could regulate aberrant alterations of these metabolites and mitigate UC via regulating metabolic pathways, including arachidonic acid and glycerophospholipid metabolism. CONCLUSION: This study provides novel evidence that SDFR could be used as a potential modulator to relieve UC. Also, the results provide a theoretical basis for the utilization of byproducts in Rosa roxburghii Tratt fruit processing. © 2024 Society of Chemical Industry.

Spatiotemporal beating and vortices of van der Waals hyperbolic polaritons.

In conventional thin materials, the diffraction limit of light constrains the number of waveguide modes that can exist at a given frequency. However, layered van der Waals (vdW) materials, such as hexagonal boron nitride (hBN), can surpass this limitation due to their dielectric anisotropy, exhibiting positive permittivity along one optic axis and negativity along the other. This enables the propagation of hyperbolic rays within the material bulk and an unlimited number of subdiffractional modes characterized by hyperbolic dispersion. By employing time-domain near-field interferometry to analyze ultrafast hyperbolic ray pulses in thin hBN, we showed that their zigzag reflection trajectories bound within the hBN layer create an illusion of backward-moving and leaping behavior of pulse fringes. These rays result from the coherent beating of hyperbolic waveguide modes but could be mistakenly interpreted as negative group velocities and backward energy flow. Moreover, the zigzag reflections produce nanoscale (60 nm) and ultrafast (40 fs) spatiotemporal optical vortices along the trajectory, presenting opportunities to chiral spatiotemporal control of light-matter interactions. Supported by experimental evidence, our simulations highlight the potential of hyperbolic ray reflections for molecular vibrational absorption nanospectroscopy. The results pave the way for miniaturized, on-chip optical spectrometers, and ultrafast optical manipulation.

Natural product Kaji-ichigoside F1 exhibits rapid antidepression via activating the AMPA-BDNF-mTOR pathway and inhibiting the NMDAR-CaMKIIα pathway.

BACKGROUND: Depression is a common and recurrent neuropsychiatric disorder. Recent studies have shown that the N-methyl-d-aspartate (NMDA) receptor (NMDAR) is involved in the pathophysiology of depression. Previous studies have found that Kaji-ichigoside F1 (KF1) has a protective effect against NMDA-induced neurotoxicity. However, the antidepressant mechanism of KF1 has not been confirmed yet. PURPOSE: In the present study, we aimed to evaluate the rapid antidepressant activity of KF1 and explore the underlying mechanism. STUDY DESIGN: First, we explored the effect of KF1 on NMDA-induced hippocampal neurons and the underlying mechanism. Second, depression was induced in C57BL/6 mice via chronic unpredictable mild stress (CUMS), and the immediate and persistent depression-like behavior was evaluated using the forced swimming test (FST) after a single administration of KF1. Third, the contributions of NMDA signaling to the antidepressant effect of KF1 were investigated using pharmacological interventions. Fourth, CUMS mice were treated with KF1 for 21 days, and then their depression-like behaviors and the underlying mechanism were further explored. METHODS: The FST was used to evaluate immediate and persistent depression-like behavior after a single administration of KF1 with or without NMDA pretreatment. The effect of KF1 on depressive-like behavior was investigated in CUMS mice by treating them with KF1 once daily for 21 days through the sucrose preference test, FST, open field test, and tail suspension test. Then, the effects of KF1 on the morphology and molecular and functional phenotypes of primary neuronal cells and hippocampus of mice were investigated by hematoxylin-eosin staining, Nissl staining, propidium iodide staining, TUNEL staining, Ca2+ imaging, JC-1 staining, ELISA, immunofluorescence analysis, RT-PCR, and Western blot. RESULTS: KF1 could effectively improve cellular viability, reduce apoptosis, inhibit the release of LDH and Ca2+, and increase the mitochondrial membrane potential and the number of dendritic spines numbers in hippocampal neurons. Moreover, behavioral tests showed that KF1 exerted acute and sustained antidepressant-like effects by reducing Glu-levels and ameliorating neuronal damage in the hippocampus. Additionally, in vivo and in vitro experiments revealed that PSD95, Syn1, α-amino-3­hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and brain-derived neurotrophic factor (BDNF) were upregulated at the protein level, and BDNF and AMPA were upregulated at the mRNA level. NR1 and NR2A showed the opposite trend. CONCLUSION: These results confirm that KF1 exerts rapid antidepressant effects mainly by activating the AMPA-BDNF-mTOR pathway and inhibiting the NMDAR-CaMKIIα pathway. This study serves as a new reference for discovering rapid antidepressants.

KF-catalyzed direct thiomethylation of carboxylic acids with DMSO to access methyl thioesters.

With dimethyl sulfoxide (DMSO) as the methylthio source, a KF-catalyzed strategy was employed for the direct thiomethylation of carboxylic acids with DMSO for the preparation of methyl thioesters. In this process, a wide range of methyl thioesters were obtained in moderate to excellent yields. This novel strategy features the first use of DMSO as a methylthiolating agent for the construction of methyl thioesters, transition metal-free conditions, inexpensive reagents, easy workup, broad substrate scope and sustainability. Additionally, this procedure can be readily scaled up to a gram scale.

Pharmacokinetics, absolute bioavailability, and tissue distribution of WJ-14, a novel N-methyl-d-aspartate receptor antagonist, in rats by liquid chromatography-tandem mass spectrometry.

To circumvent the limitations of current antidepressants, WJ-14, a novel N-methyl-d-aspartate receptor antagonist, was synthesized and demonstrated to have remarkable efficiency in the treatment of depression. To illustrate the pharmacokinetics, absolute bioavailability, and tissue distribution of WJ-14 in rats, a rapid and sensitive liquid chromatography-tandem mass spectrometry-based analytical method was developed and validated for the separation and detection of WJ-14 in both plasma and tissue samples. After oral administration, WJ-14 was rapidly absorbed into the blood with time to reach the maximum plasma concentration (Tmax ) within 0.28 h and quickly eliminated with clearance (Cl) exceeding 6.80 L/h/kg and elimination half-life (t1/2 ) within 2.69 h. No obvious accumulation was found with mean residencetime (MRT) within 4.10 h. Tissue distribution revealed that WJ-14 was extensively distributed in the main tissues of rats, and massive amounts of WJ-14 were distributed in the liver. Extensive distribution and quick elimination led to extremely low absolute bioavailability of WJ-14 (1.91% of 8.33 mg/kg and 3.30% of 24.99 mg/kg). WJ-14 was detected in the brain only 0.083 h after oral administration, which is crucial for a rapid-onset antidepressant candidate. In addition, WJ-14 likely exhibited a non-linear pharmacokinetic process at dosages of 8.33 and 24.99 mg/kg. The findings may provide valuable information for subsequent studies on WJ-14.

Venous Thrombosis Assay in a Mouse Model of Cancer.

This methodology paper highlights the surgical nuances of a rodent model of venous thrombosis, specifically in the context of cancer-associated thrombosis (CAT). Deep venous thrombosis is a common complication in cancer survivors and can be potentially fatal. The current murine venous thrombosis models typically involve a complete or partial mechanical occlusion of the inferior vena cava (IVC) using a suture. This procedure induces a total or partial stasis of blood and endothelial damage, triggering thrombogenesis. The current models have limitations such as higher variability in clot weights, significant mortality rate, and prolonged learning curve. This report introduces surgical refinements using vascular clips to address some of these limitations. Using a syngeneic colon cancer xenograft mouse model, we employed customized vascular clips to ligate the infrarenal vena cava. These clips allow residual lip space similar to a 5-0 polypropylene suture after IVC ligations. Mice with the suture method served as controls. The vascular clip method resulted in a consistent reproducible partial vascular occlusion and greater clot weights with less variability than the suture method. The larger clot weights, greater clot mass, and clot to the IVC luminal surface area were expected due to the higher pressure profile of the vascular clips compared to a 6-0 polypropylene suture. The approach was validated by gray scale ultrasonography, which revealed consistently greater clot mass in the infrarenal vena cava with vascular clips compared to the suture method. These observations were further substantiated with the immunofluorescence staining. This study offers an improved method to generate a venous thrombosis model in mice, which can be employed to deepen the mechanistic understanding of CAT and in translational research such as drug discovery.

Inhibitory effect of Incarvillea diffusa Royle extract in the formation of calcium oxalate nephrolithiasis by regulating ROS-induced Nrf2/HO-1 pathway in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Calcium oxalate (CaOx) kidney stones are widely acknowledged as the most prevalent type of urinary stones, with high incidence and recurrence rates. Incarvillea diffusa Royle (ID) is a traditionally used medicinal herb in the Miao Minzu of Guizhou province, China, for treating urolithiasis. However, the active components and the underlying mechanism of its pharmacodynamic effects remain unclear. AIM OF THE STUDY: This study aimed to investigate the potential inhibitory effect of the active component of ID on the formation of CaOx nephrolithiasis and elucidate the underlying mechanism. MATERIALS AND METHODS: In vivo, a CaOx kidney stone model was induced in Sprague-Dawley (SD) rats using an ethylene glycol and ammonium chloride protocol for four weeks. Forty-eight male SD rats were randomly assigned to 6 groups (n = 8): blank group, model group, apocynin group, and low, medium, and high dose of ID's active component (IDW) groups. After three weeks of administration, rat urine, serum, and kidney tissues were collected. Renal tissue damage and crystallization, Ox, BUN, Ca2+, CRE, GSH, MDA, SOD contents, and levels of IL-1ß, IL-18, MCP-1, caspase-1, IL-6, and TNF-α in urine, serum, and kidney tissue were assessed using HE staining and relevant assay kits, respectively. Protein expression of Nrf2, HO-1, p38, p65, and Toll-4 in kidney tissues was quantified via Western blot. The antioxidant capacities of major compounds were evaluated through DPPH, O2·-, and ·OH radical scavenging assays, along with their effects on intracellular ROS production in CaOx-induced HK-2 cells. RESULTS: We found that IDW could significantly reduce the levels of CRE, GSH, MDA, Ox, and BUN, and enhancing SOD activity. Moreover, it could inhibit the secretion of TNF-α, IL-1ß, IL-18, MCP-1, caspase-1, and decreased protein expression of Nrf2, HO-1, p38, p65, and Toll-4 in renal tissue. Three major compounds isolated from IDW exhibited promising antioxidant activities and inhibited intracellular ROS production in CaOx-induced HK-2 cells. CONCLUSIONS: IDW facilitated the excretion of supersaturated Ca2+ and decreased the production of Ox, BUN in SD rat urine, and mitigated renal tissue damage by regulating Nrf2/HO-1 signaling pathway. Importantly, the three major compounds identified as active components of IDW contributed to the inhibition of CaOx nephrolithiasis formation. Overall, IDW holds significant potential for treating CaOx nephrolithiasis.

Association of concomitant continuous pain in trigeminal neuralgia with a narrow foramen ovale.

Background: The pathogenesis of concomitant continuous pain remains unclear and is worthy of further study. In this clinical study, we aimed to explore the potential role of a narrow foramen ovale in the development of concomitant continuous pain. Methods: A total of 108 patients with classical trigeminal neuralgia affecting the third branch of the trigeminal nerve and 46 healthy individuals were enrolled in this study. Three-dimensional reconstructed computerized tomography images of all participants were collected, and the morphometric features of the foramen ovale were examined by two investigators who were blinded to the clinical data of the patients. Results: In this cohort, patients with concomitant continuous pain suffered from more sensory abnormalities (18.4% vs. 2.9%, p = 0.015) and responded more poorly to medication (74.3% vs. 91.9%, p = 0.018) than patients without concomitant continuous pain. While no significant differences regarding the mean length (5.02 mm vs. 5.36 mm, p > 0.05) and area (22.14 mm2 vs. 23.80 mm2, p > 0.05) were observed between patients with and without concomitant continuous pain, the mean width of the foramen ovale on the affected side in patients with concomitant continuous pain was significantly narrower than that in patients without concomitant continuous pain (2.01 mm vs. 2.48 mm, p = 0.003). Conclusion: This neuroimaging and clinical study demonstrated that the development of concomitant continuous pain was caused by the compression of the trigeminal nerve owing to a narrow foramen ovale rather than responsible vessels in classical trigeminal neuralgia.

[Chemical constituents and their α-glucosidase inhibitory activities of seeds of Moringa oleifera].

The chemical constituents of the seeds of Moringa oleifera were isolated and purified by using Sephadex LH-20, Toyo-pearl HW-40F, silica gel, ODS, and MCI column chromatography. The structures of compounds were identified by high-resolution mass spectrometry, ~1H-NMR, ~(13)C-NMR, HMQC, HMBC, and ~1H-~1H COSY, as well as physicochemical properties of compounds and literature data. Twelve compounds were isolated from 30% ethanol fraction of the seeds of M. oleifera and identified as ethyl-4-O-α-L-rhamnosyl-α-L-rhamnoside(1), ethyl-3-O-α-L-rhamnosyl-α-L-rhamnoside(2),(4-hydroxybenzyl)ethyl carbamate(3),(4-aminophenyl)acetic acid(4), ethyl-α-L-rhamnoside(5), methyl-α-L-rhamnoside(6), moringapyranosyl(7), 2-[4-(α-L-rhamnosyl)phenyl]methyl acetate(8), niaziridin(9), 5-hydroxymethyl furfural(10), 4-hydroxybenzeneacetamide(11), and 4-hydroxybenzoic acid(12). Among them, compounds 1 and 2 are two new compounds, compound 3 is a new natural product, and compounds 4-5 were yielded from Moringa plant for the first time. All compounds were evaluated for α-glucosidase inhibitory activity in vitro. Compound 10 showed excellent inhibitory activity with IC_(50) of 210 µg·mL~(-1).

Six New Phenolic Glycosides from the Seeds of Moringa oleifera Lam. and Their α-Glucosidase Inhibitory Activity.

Plant-derived phytochemicals have recently drawn interest in the prevention and treatment of diabetes mellitus (DM). The seeds of Moringa oleifera Lam. are widely used in food and herbal medicine for their health-promoting properties against various diseases, including DM, but many of their effective constituents are still unknown. In this study, 6 new phenolic glycosides, moringaside B-G (1-6), together with 10 known phenolic glycosides (7-16) were isolated from M. oleifera seeds. The structures were elucidated by 1D and 2D NMR spectroscopy and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) data analysis. The absolute configurations of compounds 2 and 3 were determined by electronic circular dichroism (ECD) calculations. Compounds 2 and 3 especially are combined with a 1,3-dioxocyclopentane moiety at the rhamnose group, which are rarely reported in phenolic glycoside backbones. A biosynthetic pathway of 2 and 3 was assumed. Moreover, all the isolated compounds were evaluated for their inhibitory activities against α-glucosidase. Compounds 4 and 16 exhibited marked activities with IC50 values of 382.8 ± 1.42 and 301.4 ± 6.22 µM, and the acarbose was the positive control with an IC50 value of 324.1 ± 4.99 µM. Compound 16 revealed better activity than acarbose.

Tryptophan Metabolites Target Transmembrane and Immunoglobulin Domain-Containing 1 Signaling to Augment Renal Tubular Injury.

Chronic kidney disease (CKD) is characterized by the accumulation of uremic toxins and renal tubular damage. Tryptophan-derived uremic toxins [indoxyl sulfate (IS) and kynurenine (Kyn)] are well-characterized tubulotoxins. Emerging evidence suggests that transmembrane and immunoglobulin domain-containing 1 (TMIGD1) protects tubular cells and promotes survival. However, the direct molecular mechanism(s) underlying how these two opposing pathways crosstalk remains unknown. We posited that IS and Kyn mediate tubular toxicity through TMIGD1 and the loss of TMIGD1 augments tubular injury. Results from the current study showed that IS and Kyn suppressed TMIGD1 transcription in tubular cells in a dose-dependent manner. The wild-type CCAAT enhancer-binding protein ß (C/EBPß) enhanced, whereas a dominant-negative C/EBPß suppressed, TMIGD1 promoter activity. IS down-regulated C/EBPß in primary human renal tubular cells. The adenine-induced CKD, unilateral ureteric obstruction, and deoxycorticosterone acetate salt unilateral nephrectomy models showed reduced TMIGD1 expression in the renal tubules, which correlated with C/EBPß expression. C/EBPß levels negatively correlated with the IS and Kyn levels. Inactivation of TMIGD1 in mice significantly lowered acetylated tubulin, decreased tubular cell proliferation, caused severe tubular damage, and worsened renal function. Thus, the current results demonstrate that TMIGD1 protects renal tubular cells from renal injury in different models of CKD and uncovers a novel mechanism of tubulotoxicity of tryptophan-based uremic toxins.

Optical nanoimaging of highly-confined phonon polaritons in atomically-thin nanoribbons of α-MoO3.

Phonon polaritons (PhPs), collective modes hybridizing photons with lattice vibrations in polar insulators, enable nanoscale control of light. In recent years, the exploration of in-plane anisotropic PhPs has yielded new levels of confinement and directional manipulation of nano-light. However, the investigation of in-plane anisotropic PhPs at the atomic layer limit is still elusive. Here, we report the optical nanoimaging of highly-confined phonon polaritons in atomically-thin nanoribbons of α-MoO3 (5 atomic layers). We show that narrow α-MoO3 nanoribbons as thin as a few atomic layers can support anisotropic PhPs modes with a high confinement ratio (∼133 times smaller wavelength than that of light). The anisotropic PhPs interference fringe patterns in atomic layers are tunable depending on the PhP wavelength via changing the illumination frequency. Moreover, spatial control over the PhPs interference patterns is also achieved by varying the nanostructures' shape or nanoribbon width of atomically-thin α-MoO3. Our work may serve as an empirical reference point for other anisotropic PhPs that approach the thickness limit and pave the way for applications such as atomically integrated nano-photonics and sensing.

Ultrafast anisotropic dynamics of hyperbolic nanolight pulse propagation.

Polariton pulses-transient light-matter hybrid excitations-traveling through anisotropic media can lead to unusual optical phenomena in space and time. However, studying these pulses presents challenges with their anisotropic, ultrafast, and nanoscale field variations. Here, we demonstrate the creation, observation, and control of polariton pulses, with in-plane hyperbolic dispersion, on anisotropic crystal surfaces by using a time-resolved nanoimaging technique and our developed high-dimensional data processing. We capture and analyze movies of distinctive pulse spatiotemporal dynamics, including curved ultraslow energy flow trajectories, anisotropic dissipation, and dynamical misalignment between phase and group velocities. Our approach enables analysis of polariton pulses in the wave vector time domain, demonstrating a time-domain polaritonic topological transition from lenticular to hyperbolic dispersion contours and the ability to study the polariton-induced time-varying optical forces. Our findings promise to facilitate the study of diverse space-time phenomena at extreme scales and drive advances in ultrafast nanoimaging.

Design, synthesis and evaluation of novel 1-phenyl-pyrrolo[1,2-b]isoquinolin-3-one derivatives as antagonists for the glycine binding site of the NMDA receptor.

A new series of 1-phenyl-pyrrolo[1,2-b]isoquinolin-3-one derivatives were designed, synthesized and demonstrated to act as antagonists for the glycine binding site of the NMDA receptor. These new derivatives protected PC12 cells against NMDA-induced injury and cell apoptosis in vitro, among which compound 13b exhibited excellent cytoneuroprotective potency and shown a dose-dependent prevention. The increased intracellular Ca2+ influx caused by NMDA in PC12 cells was reversed when pretreated with compound 13b. Furthermore, the interaction between compound 13b and the glycine binding site of the NMDA receptor was validated via MST assay. It was observed that the stereochemistry of compound 13b did not influence the binding affinity, which was consistent with the neuroprotective result. Molecular docking study confirmed the observed activity of compound 13b by virtue of their Pi-stacking, cation-Pi, H-bonding and Pi-electron interactions with the key amino acids in the glycine binding pocket. These results confirm the potential of 1-phenyl-pyrrolo[1,2-b]isoquinolin-3-one derivatives as neuroprotective agents targeting the glycine binding site of the NMDA receptor.

Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype.

Introduction: The current approaches that are used to treat ischemic stroke suffer from poor targeting, lack of effectiveness, and potential off-target effects, necessitating the development of new therapeutic strategies to enhance neuronal cell survival and regeneration. This study aimed to investigate the role of microglial Netrin-1 in ischemic stroke, a topic that has not been fully understood. Methods: Netrin-1 levels and its primary receptor expressions were investigated in cerebral microglia from acute ischemic stroke patients and age-matched control subjects. A public database (GEO148350), which supplied RNAseq results for rat cerebral microglia in a middle cerebral artery occlusion (MCAO) model, was analyzed to assess the expression of Netrin-1, its major receptors, and genes related to macrophage function. A microglia-specific gene targeting approach and a delivery system allowing for crossing the blood-brain barrier were applied in a mouse model for ischemic stroke to investigate the role of microglial Netrin-1. Netrin-1 receptor signaling in microglia was observed and the effects on microglial phenotype, apoptosis, and migration were analyzed. Results: Across human patients, rat and mouse models, activation of Netrin-1 receptor signaling was mainly conducted via its receptor UNC5a in microglia, which resulted in a shift in microglial phenotype towards an anti-inflammatory or M2-like state, leading to a reduction in apoptosis and migration of microglia. Netrin-1-induced phenotypic change in microglia exerted protective effects on neuronal cells in vivo during ischemic stroke. Conclusion: Our study highlights the potential of targeting Netrin-1 and its receptors as a promising therapeutic strategy for promoting post-ischemic survival and functional recovery.