Long-term exposure to cadmium disrupts neurodevelopment in mature cerebral organoids.

Cadmium (Cd) is a pervasive environmental pollutant. Increasing evidence suggests that Cd exposure during pregnancy can induce adverse neurodevelopmental outcomes. However, due to the limitations of neural cell and animal models, it is challenging to study the developmental neurotoxicity and underlying toxicity mechanism of long-term exposure to environmental pollutants during human brain development. In this study, chronic Cd exposure was performed in human mature cerebral organoids for 49 or 77 days. Our study found that prolonged exposure to Cd resulted in the inhibition of cerebral organoid growth and the disruption of neural differentiation and cortical layer organization. These potential consequences of chronic Cd exposure may include impaired GFAP expression, a reduction in SOX2+ neuronal progenitor cells, an increase in TUJ1+ immature neurons, as well as an initial increase and a subsequent decrease in both TBR2+ intermediate progenitors and CTIP2+ deep layer cortical neurons. Transcriptomic analyses revealed that long-term exposure to Cd disrupted zinc and copper ion homeostasis through excessive synthesis of metallothionein and disturbed synaptogenesis, as evidenced by inhibited postsynaptic protein. Our study employed mature cerebral organoids to evaluate the developmental neurotoxicity induced by long-term Cd exposure.

Hippocampal circAnk3 Deficiency Causes Anxiety-like Behaviors and Social Deficits by Regulating the miR-7080-3p/IQGAP1 Pathway in Mice.

BACKGROUND: Circular RNAs are highly enriched in the synapses of the mammalian brain and play important roles in neurological function by acting as molecular sponges of microRNAs. circAnk3 is derived from the 11th intron of the ankyrin-3 gene, Ank3, a strong genetic risk factor for neuropsychiatric disorders; however, the function of circAnk3 remains elusive. In this study, we investigated the function of circAnk3 and its downstream regulatory network for target genes in the hippocampus of mice. METHODS: The DNA sequence from which circAnk3 is generated was modified using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9) technology, and neurobehavioral tests (anxiety and depression-like behaviors, social behaviors) were performed in circAnk3+/- mice. A series of molecular and biochemical assays were used to investigate the function of circAnk3 as a microRNA sponge and its downstream regulatory network for target genes. RESULTS: circAnk3+/- mice exhibited both anxiety-like behaviors and social deficits. circAnk3 was predominantly located in the cytoplasm of neuronal cells and functioned as a miR-7080-3p sponge to regulate the expression of Iqgap1. Inhibition of miR-7080-3p or restoration of Iqgap1 in the hippocampus ameliorated the behavioral deficits of circAnk3+/- mice. Furthermore, circAnk3 deficiency decreased the expression of the NMDA receptor subunit GluN2a and impaired the structural plasticity of dendritic synapses in the hippocampus. CONCLUSIONS: Our results reveal an important role of the circAnk3/miR-7080-3p/IQGAP1 axis in maintaining the structural plasticity of hippocampal synapses. circAnk3 might offer new insights into the involvement of circular RNAs in neuropsychiatric disorders.

Neurodevelopmental defects in human cortical organoids with N-acetylneuraminic acid synthase mutation.

Biallelic genetic variants in N-acetylneuraminic acid synthase (NANS), a critical enzyme in endogenous sialic acid biosynthesis, are clinically associated with neurodevelopmental disorders. However, the mechanism underlying the neuropathological consequences has remained elusive. Here, we found that NANS mutation resulted in the absence of both sialic acid and protein polysialylation in the cortical organoids and notably reduced the proliferation and expansion of neural progenitors. NANS mutation dysregulated neural migration and differentiation, disturbed synapse formation, and weakened neuronal activity. Single-cell RNA sequencing revealed that NANS loss of function markedly altered transcriptional programs involved in neuronal differentiation and ribosomal biogenesis in various neuronal cell types. Similarly, Nans heterozygous mice exhibited impaired cortical neurogenesis and neurobehavioral deficits. Collectively, our findings reveal a crucial role of NANS-mediated endogenous sialic acid biosynthesis in regulating multiple features of human cortical development, thus linking NANS mutation with its clinically relevant neurodevelopmental disorders.

Methamphetamine exposure drives cell cycle exit and aberrant differentiation in rat hippocampal-derived neurospheres.

Introduction: Methamphetamine (METH) abuse by pregnant drug addicts causes toxic effects on fetal neurodevelopment; however, the mechanism underlying such effect of METH is poorly understood. Methods: In the present study, we applied three-dimensional (3D) neurospheres derived from the embryonic rat hippocampal tissue to investigate the effect of METH on neurodevelopment. Through the combination of whole genome transcriptional analyses, the involved cell signalings were identified and investigated. Results: We found that METH treatment for 24 h significantly and concentration-dependently reduced the size of neurospheres. Analyses of genome-wide transcriptomic profiles found that those down-regulated differentially expressed genes (DEGs) upon METH exposure were remarkably enriched in the cell cycle progression. By measuring the cell cycle and the expression of cell cycle-related checkpoint proteins, we found that METH exposure significantly elevated the percentage of G0/G1 phase and decreased the levels of the proteins involved in the G1/S transition, indicating G0/G1 cell cycle arrest. Furthermore, during the early neurodevelopment stage of neurospheres, METH caused aberrant cell differentiation both in the neurons and astrocytes, and attenuated migration ability of neurospheres accompanied by increased oxidative stress and apoptosis. Conclusion: Our findings reveal that METH induces an aberrant cell cycle arrest and neuronal differentiation, impairing the coordination of migration and differentiation of neurospheres.

Morphine Re-arranges Chromatin Spatial Architecture of Primate Cortical Neurons.

The expression of linear DNA sequence is precisely regulated by the three-dimensional (3D) architecture of chromatin. Morphine-induced aberrant gene networks of neurons have been extensively investigated; however, how morphine impacts the 3D genomic architecture of neurons is still unknown. Here, we applied digestion-ligation-only high-throughput chromosome conformation capture (DLO Hi-C) technology to investigate the effects of morphine on the 3D chromatin architecture of primate cortical neurons. After receiving continuous morphine administration for 90 days on rhesus monkeys, we discovered that morphine re-arranged chromosome territories, with a total of 391 segmented compartments being switched. Morphine altered over half of the detected topologically associated domains (TADs), most of which exhibited a variety of shifts, followed by separating and fusing types. Analysis of the looping events at kilobase-scale resolution revealed that morphine increased not only the number but also the length of differential loops. Moreover, all identified differentially expressed genes from the RNA sequencing data were mapped to the specific TAD boundaries or differential loops, and were further validated for changed expression. Collectively, an altered 3D genomic architecture of cortical neurons may regulate the gene networks associated with morphine effects. Our finding provides critical hubs connecting chromosome spatial organization and gene networks associated with the morphine effects in humans.

Assessment of iris volume in glaucoma patients with type 2 diabetes mellitus by AS-OCT.

AIM: To examine the change of iris volume measured by CASIA2 anterior segment optical coherence tomography (AS-OCT) in glaucoma patients with or without type 2 diabetes mellitus (T2DM) and explore if there is a correlation between hemoglobin A1c (HbA1c) level and iris volume. METHODS: In a cross-sectional study, 72 patients (115 eyes) were divided into two groups: primary open angle glaucoma (POAG) group (55 eyes) and primary angle-closure glaucoma (PACG) group (60 eyes). Patients in each group were separately classified into patients with or without T2DM. Iris volume and glycosylated HbA1c level were measured and analyzed. RESULTS: In the PACG group, diabetic patients' iris volume was significantly lower than those of non-diabetics (P=0.02), and there was a significant correlation between iris volume and HbA1c level in the PACG group (r=-0.26, P=0.04). However, diabetic POAG patients' iris volume was noticeably higher than those of non-diabetics (P=0.01), and there was a significant correlation between HbA1c level and iris volume (r=0.32, P=0.02). CONCLUSION: Diabetes mellitus impact iris volume size, as seen by increased iris volume in the POAG group and decreased iris volume in the PACG group. In addition, iris volume is significantly correlated with HbA1c level in glaucoma patients. These findings imply that T2DM may compromise iris ultrastructure in glaucoma patients.

Purification and Identification of Novel Antioxidant Peptides from Hydrolysates of Peanuts (Arachis hypogaea) and Their Neuroprotective Activities.

Peanut (Arachis hypogaea) peptides have various functional activities and a high utilization value. This study aims to isolate and characterize antioxidant peptides from peanut protein hydrolysates and further evaluate their neuroprotection against oxidative damage to PC12 cells induced by 6-hydroxydopamine (6-OHDA). After the peanut protein was hydrolyzed with pepsin and purified using ultrafiltration and gel chromatography, six peptides were identified and sequenced by high-performance liquid chromatography (HPLC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Out of these six peptides, Pro-Gly-Cys-Pro-Ser-Thr (PGCPST) exhibited a desirable antioxidant capacity, as determined using the 1,1-diphenyl-2-picrylhydrazyl, 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt, and hydroxyl radical scavenging assays. Moreover, our results indicated that the peptide PGCPST effectively increased the cell viability and reduced the cell apoptosis in 6-OHDA-induced PC12. RNA sequencing further showed that the neuroprotective effect of the peptide PGCPST was mediated via sphingolipid metabolism-related pathways. With further research efforts, the peptide PGCPST was expected to develop into a new neuroprotective agent.

Cardiolipin and OPA1 Team up for Methamphetamine-Induced Locomotor Activity by Promoting Neuronal Mitochondrial Fusion in the Nucleus Accumbens of Mice.

Mitochondria are highly dynamic organelles with coordinated cycles of fission and fusion occurring continuously to satisfy the energy demands in the complex architecture of neurons. How mitochondria contribute to addicted drug-induced adaptable mitochondrial networks and neuroplasticity remains largely unknown. Through liquid chromatography-mass spectrometry-based lipidomics, we first analyzed the alteration of the mitochondrial lipidome of three mouse brain areas in methamphetamine (METH)-induced locomotor activity and conditioned place preference. The results showed that METH remodeled the mitochondrial lipidome of the hippocampus, nucleus accumbens (NAc), and striatum in both models. Notably, mitochondrial hallmark lipid cardiolipin (CL) was specifically increased in the NAc in METH-induced hyperlocomotor activity, which was accompanied by an elongated giant mitochondrial morphology. Moreover, METH significantly boosted mitochondrial respiration and ATP generation as well as the copy number of mitochondrial genome DNA in the NAc. By screening the expressions of mitochondrial dynamin-related proteins, we found that repeated METH significantly upregulated the expression of long-form optic atrophy type 1 (L-OPA1) and enhanced the interaction of L-OPA1 with CL, which may promote mitochondrial fusion in the NAc. On the contrary, neuronal OPA1 depletion in the NAc not only recovered the dysregulated mitochondrial morphology and synaptic vesicle distribution induced by METH but also attenuated the psychomotor effect of METH. Collectively, upregulated CL and OPA1 cooperate to mediate METH-induced adaptation of neuronal mitochondrial dynamics in the NAc, which correlates with the psychomotor effect of METH. These findings propose a potential therapeutic approach for METH addiction by inhibiting neuronal mitochondrial fusion.

Antibacterial Mechanism of 2R,3R-Dihydromyricetin Against Staphylococcus aureus: Deciphering Inhibitory Effect on Biofilm and Virulence Based on Transcriptomic and Proteomic Analyses.

Staphylococcus aureus is a major foodborne pathogen that leads to various diseases due to its biofilm and virulence factors. This study aimed to investigate the inhibitory effect of 2R,3R-dihydromyricetin (DMY), a natural flavonoid compound, on the biofilm formation and virulence of S. aureus, and to explore the mode of action using transcriptomic and proteomic analyses. Microscopic observation revealed that DMY could remarkably inhibit the biofilm formation by S. aureus, leading to a collapse on the biofilm architecture and a decrease in viability of biofilm cell. Moreover, the hemolytic activity of S. aureus was reduced to 32.7% after treatment with subinhibitory concentration of DMY (p < 0.01). Bioinformation analysis based on RNA-sequencing and proteomic profiling revealed that DMY induced 262 differentially expressed genes and 669 differentially expressed proteins (p < 0.05). Many downregulated genes and proteins related to surface proteins were involved in biofilm formation, including clumping factor A (ClfA), iron-regulated surface determinants (IsdA, IsdB, and IsdC), fibrinogen-binding proteins (FnbA, FnbB), and serine protease. Meanwhile, DMY regulated a wide range of genes and proteins enriched in bacterial pathogenesis, cell envelope, amino acid metabolism, purine and pyrimidine metabolism, and pyruvate metabolism. These findings suggest that DMY targets S. aureus through multifarious mechanisms, and especially prompt that interference of surface proteins in cell envelope would lead to attenuation of biofilm and virulence.

Insights into peptide profiling of sturgeon myofibrillar proteins with low temperature vacuum heating.

BACKGROUND: Protein oxidation during food processing causes changes in the balance of protein-molecular interactions and protein-water interactions, ultimately leading to protein denaturation, which results in the loss of a range of functional properties. Therefore, how to control the oxidative modification of proteins during processing has been the focus of research. RESULTS: In the present study, the intrinsic fluorescence value of the myofibrillar proteins (MP) decreased and the surface hydrophobicity value increased, indicating that the heat treatment caused a significant change in the conformation of the MP. With an increase in heating temperature, protein carbonyl content increased, total sulfhydryl content decreased, and protein secondary structure changed from α-helix to ß-sheet, indicating that protein oxidation and aggregation occurred. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that heat treatment can lead to the degradation of proteins, especially myosin heavy chain, although actin had a certain thermal stability. In total, 733 proteins were identified by proteomics, and the protein oxidation caused by low temperature vacuum heating (LTVH) was determined to be mild oxidation dominated by malondialdehyde and 4-hydroxynonenal by oxidation site division. CONCLUSION: The present study has revealed the effect of LTVH treatment on the protein oxidation modification behavior of sturgeon meat, and explored the effect mechanism of LTVH treatment on the processing quality of sturgeon meat from the perspective of protein oxidation. The results may provide a theoretical basis for the precise processing of aquatic products. © 2023 Society of Chemical Industry.

Insight into structural characteristics of theabrownin from Pingwu Fuzhuan brick tea and its hypolipidemic activity based on the in vivo zebrafish and in vitro lipid digestion and absorption models.

Fuzhuan brick tea (FBT) is a post-fermented dark tea preferred by consumers for its excellent hypolipidemic activity, and theabrownin (TB) is the main bioactive composition in FBT. This work explored the structural and hypolipidemic properties of TB derived from Pingwu FBT, and investigated whether it exerted hypolipidemic activity by inhibiting intestinal lipid absorption. Structural characterization revealed that TB was an amorphous polymerized phenolic compound rich in hydroxyl and carboxyl groups with good thermostability. In vivo, TB and its fractions with different molecular weights (TB-LT3k, TB-3-10k, TB-10-30k, TB-30-100k, TB-GT100k) significantly reduced the lipid levels of hyperlipidemia zebrafish (P < 0.05). Moreover, TB attenuated hyperlipidemia by inhibiting intestinal lipid absorption, as TB effectively bound to bile acids, inhibited enzymatic activity of pancreatic lipase and cholesterol esterase, influenced micelle formation, and decreased micellar cholesterol solubility. Results facilitated research on TB and offered support for its feasibility as a natural alternative to prevent hyperlipidemia.

Integrated lipidomic and transcriptomic analysis reveals clarithromycin-induced alteration of glycerophospholipid metabolism in the cerebral cortex of mice.

Clarithromycin (CLA) has been widely used in the treatment of bacterial infection. Research reveals the adverse effects on the central nervous system among patients receiving CLA treatment; whereas, a relevant underlying mechanism remains considerably unclear. According to our research, an integrated lipidomic and transcriptomic analysis was applied to explore the effect of CLA on neurobehavior. CLA treatment caused anxiety-like behaviors dose-dependently during open field as well as elevated plus maze trials on mice. Transcriptomes and LC/MS-MS-based metabolomes were adopted for investigating how CLA affected lipidomic profiling as well as metabolic pathway of the cerebral cortex. CLA exposure greatly disturbed glycerophospholipid metabolism and the carbon chain length of fatty acids. By using whole transcriptome sequencing, we found that CLA significantly downregulated the mRNA expression of CEPT1 and CHPT1, two key enzymes involved in the synthesis of glycerophospholipids, supporting the findings from the lipidomic profiling. Also, CLA causes changes in neuronal morphology and function in vitro, which support the existing findings concerning neurobehavior in vivo. We speculate that altered glycerophospholipid metabolism may be involved in the neurobehavioral effect of CLA. Our findings contribute to understanding the mechanisms of CLA-induced adverse effects on the central nervous system. 1. Clarithromycin treatment caused anxiety-like behavior with dose-dependent response both in the open field and elevated plus maze test in mice; 2. Clarithromycin exposing predominately disturbed the metabolism of glycerophospholipids in the cerebral cortex of mice; 3. Clarithromycin application remarkably attenuated CEPT1 and CHPT1 gene expression, which participate in the last step in the synthesis of glycerophospholipids; 4. The altered glycerophospholipid metabolomics may be involved in the abnormal neurobehavior caused by clarithromycin.

Neonatal exposure to sevoflurane induces adolescent neurobehavioral dysfunction by interfering with hippocampal glycerophoslipid metabolism in rats.

Sevoflurane exposure in the neonatal period causes long-term developmental neuropsychological dysfunction, including memory impairment and anxiety-like behaviors. However, the molecular mechanisms underlying such effects have not been fully elucidated. In this study, we investigated the effect of neonatal exposure to sevoflurane on neurobehavioral profiles in adolescent rats, and applied an integrated approach of lipidomics and proteomics to investigate the molecular network implicated in neurobehavioral dysfunction. We found that neonatal exposure to sevoflurane caused cognitive impairment and social behavior deficits in adolescent rats. Lipidomics analyses revealed that sevoflurane significantly remodeled hippocampal lipid metabolism, including lysophatidylcholine (LPC) metabolism, phospholipid carbon chain length and carbon chain saturation. Through a combined proteomics analysis, we found that neonatal exposure to sevoflurane significantly downregulated the expression of lysophosphatidylcholine acyltransferase 1 (LPCAT1), a key enzyme in the regulation of phospholipid metabolism, in the hippocampus of adolescent rats. Importantly, hippocampal LPCAT1 overexpression restored the dysregulated glycerophospholipid (GP) metabolism and alleviated the learning and memory deficits caused by sevoflurane. Collectively, our evidence that neonatal exposure to sevoflurane downregulates LPCAT1 expression and dysregulates GP metabolism in the hippocampus, which may contribute to the neurobehavioral dysfunction in the adolescent rats.

Interaction and binding mechanism of lipid oxidation products to sturgeon myofibrillar protein in low temperature vacuum heating conditions: Multispectroscopic and molecular docking approaches.

In this work, the binding mechanism of myofibrillar protein (MP) with malondialdehyde and 4-hydroxy-2-nonenal under low temperature vacuum heating was investigated via multispectroscopic and molecular docking. The results showed that binding interaction and increasing temperature caused significant changes in the conformations as well as a decrease in the value of protein intrinsic fluorescence, surface hydrophobicity, and fluorescence excitation-emission matrix spectra. Furthermore, the decrease in α-helix and ß-turn, increase in ß-sheet and a random coil of MP, imply the MP molecules to be more unfolded. Isothermal titration calorimetry and molecular docking results showed that main driving force for binding with MP was hydrogen bond, and the binding ability of malondialdehyde was superior to that of 4-hydroxy-2-nonenal. Moreover, increasing the heating temperature was beneficial to the binding reaction and intensified the conformational transition of MP. These results will provide a reference for further studies on the lipid and protein interaction of sturgeon.

Regulatory effects of miRNA-126 on Th cell differentiation and cytokine expression in allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a common disease worldwide. Imbalances in T helper (Th) cell differentiation and the dysregulation of related cytokines form the immunological basis of AR. miR-126 may play an important regulatory role in AR as a new marker and predictor of the disease. Therefore, the aim of this study was to explore the regulatory effects of miR-126 on Th cell differentiation and cytokine expression in AR. METHODS: T lymphocytes and rat models were transfected with a miR-126 mimic and an inhibitor. The expression of miR-126 and Th cell-related cytokines was detected by RT-qPCR and western blotting. The serum IgE levels were detected using ELISA. In the nasal mucosa, pathological changes were observed by HE staining, protein expression was detected by immunohistochemistry, and the differentiation ratio of Th cell subsets was detected by flow cytometry. RESULTS: During the occurrence and development of AR, the expression of miR-126 and the IgE levels were increased in the AR group. The number of Treg cell subsets decreased in the AR rats, increased after the miR-126 agomir intervention and decreased after miR-126 antagomir intervention. The number of Th1 and Th2 cell subsets increased in the AR rats, decreased after miR-126 agomir intervention and increased after the miR-126 antagomir intervention. CONCLUSION: We propose that miR-126 may be involved in the pathogenesis of AR by positively regulating the expression of Treg cytokines and negatively regulating the expression of the Th1 and Th2 cytokines.

Silver nanoparticles exposure induces developmental neurotoxicity in hiPSC-derived cerebral organoids.

Silver nanoparticles (AgNPs) are used in various research fields. Although the neurotoxicity of AgNPs has been explored in animal models and 2D cell-culture models, including human stem cells, these models cannot accurately mimic the development of the human brain. Therefore, the potential mechanisms of AgNPs-induced developmental neurotoxicity in humans are still largely unclear. In this study, cerebral organoids derived from induced pluripotent stem cells were treated with 0.1 µg/mL or 0.5 µg/mL AgNPs for 7 days. At the low concentration (0.1 µg/mL), AgNPs increased the cell proliferation and inhibited the neural apoptosis in the organoids, but impaired the cilium assembly and elongation, which may perturb the cell cycle and induce abnormal cerebral-organoid growth. Conversely, at the high concentration (0.5 µg/mL), AgNPs significantly inhibited cell proliferation and induced apoptosis in cerebral organoids. High-concentration AgNPs reduced the expression and co-localization of the cytoskeleton proteins F-actin, myosin, and tubulin, thereby perturbing neurite growth. In conclusion, AgNPs exposure induces developmental neurotoxic effects in cerebral organoids and is thus a potential congenital risk factor.

Identification of novel antioxidant peptides from sea squirt (Halocynthia roretzi) and its neuroprotective effect in 6-OHDA-induced neurotoxicity.

Ocean life contains a wealth of bioactive peptides that could be utilized in nutraceuticals and pharmaceuticals. This study aimed to obtain neuroprotective antioxidant peptides in sea squirt (Halocynthia roretzi) through protamex enzymolysis. Fraction F4 (ultrafiltration generated four fractions) had a lower molecular weight (<500 Dalton (Da)) with greater 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) radical scavenging activities (94.24 ± 2.50% and 91.80 ± 1.19%). After gel filtration, six peptides, including Phe-Gly-Phe (FGF), Leu-Gly-Phe (LGF), Leu-Phe-VAL (LFV), Val-Phe-Leu (VFL), Trp-Leu-Pro (WLP), and Ile-Ser-Trp (ISW), were identified and sequenced by liquid chromatography-mass spectrometry (LC-MS/MS). Peptides WLP and ISW showed higher oxygen radical absorbance capacity (ORAC) values (2.72 ± 0.47 and 1.93 ± 0.01 µmol L-1 of Trolox equivalent (TE) per µmol L-1 of peptide) than glutathione (GSH). Additionally, WLP effectively increased cell viability, dramatically attenuated 6-Hydroxydopamine (6-OHDA)-induced cell apoptosis and decreased reactive oxygen species (ROS) levels to nearly two-fold, and significantly boosted glutathione peroxidase (GSH-Px) activity in PC12 cells. Transcriptome sequencing revealed differential expression of genes associated with various oxidative stress pathways after WLP treatment, such as glutathione metabolism. These results suggest that the Halocynthia roretzi-derived tripeptide WLP could alleviate neurodegenerative diseases associated with oxidative stress.

Synapse differentiation-induced gene 1 regulates stress-induced depression through interaction with the AMPA receptor GluA2 subunit of nucleus accumbens in male mice.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are key regulators during the process of synaptic plasticity in major depression disorder (MDD). Synapse differentiation-induced gene 1 (SynDIG1) functions as an atypical AMPAR auxiliary subunit and regulates synaptic AMPAR content; however, the role of SynDIG1 in MDD remains elusive. In this study, we found that the SynDIG1 expression was significantly increased in the neurons of the nucleus accumbens (NAc) of male mice after chronic social defeat stress (CSDS). CSDS enhanced SynDIG1-GluA2 binding and promoted the surface expression of AMPAR subunit GluA2 in the NAc. Knockdown of SynDIG1 decreased the surface expression of GluA2 and reversed the alteration of dendrite spines in the neurons, eventually alleviating the depressive-like behaviors of the stressed mice. Moreover, intra-NAc injection of IP12, a specific peptide to disrupt the interaction of SynDIG1 with GluA2, rescued depressive-like behaviors. Collectively, SynDIG1 regulates the surface expression of GluA2 and dendritic remodeling in the NAc of male mice under CSDS, thus mediating the depressive-like behaviors.

Rational Design of Quinoxalinone-Based Red-Emitting Probes for High-Affinity and Long-Term Visualizing Amyloid-ß In Vivo.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with insidious onset, and the deposition of amyloid-ß (Aß) is believed to be one of the main cause. Fluorescence imaging is a promising technique for this task, but the Aß gold standard probe ThT developed based on this still has shortcomings. The development of a new fluorescent probe to detect Aß plaques is thought to be essential. Herein, a series of red to near-infrared emitting fluorescent probes QNO-ADs with newly quinoxalinone skeleton are designed to detect Aß plaques. They all demonstrate excellent optical properties and high binding affinity (∼Kd = 20 nM) to Aß aggregates. As the most outstanding candidate, QNO-AD-3 shows significant signal-to-noise (S/N) ratio at the level of in vitro binding studies, and the brilliant fluorescence staining results in favor of grasping the approximate distribution of Aß plaques in the brain slice. In vivo Aß plaques imaging suggests that QNO-AD-3 can cross the BBB and have a long retention time in the brain with low biological toxicity. In addition, the results of docking theoretical calculation also provide some references for the design of Aß probe. Overall, given the high affinity of QNO-AD-3 and the ability to monitor Aß plaques for a long time that is not common now, we believe QNO-AD-3 will be an effective tool for an Aß-related matrix and AD disease research in the future.

Lipidomics Reveals Dysregulated Glycerophospholipid Metabolism in the Corpus Striatum of Mice Treated with Cefepime.

Cefepime exhibits a broad spectrum of antimicrobial activity and thus is a widely used treatment for severe bacterial infections. Adverse effects on the central nervous system (CNS) have been reported in patients treated with cefepime. Current explanation for the adverse neurobehavioral effect of cefepime is mainly attributed to its ability to cross the blood-brain barrier and competitively bind to the GABAergic receptor; however, the underlying mechanism is largely unknown. In this study, mice were intraperitoneally administered 80 mg/kg cefepime for different periods, followed by neurobehavioral tests and a brain lipidomic analysis. LC/MS-MS-based metabolomics was used to investigate the effect of cefepime on the brain lipidomic profile and metabolic pathways. Repeated cefepime treatment time-dependently caused anxiety-like behaviors, which were accompanied by reduced locomotor activity in the open field test. Cefepime profoundly altered the lipid profile, acyl chain length, and unsaturation of fatty acids in the corpus striatum, and glycerophospholipids accounted for a large proportion of those significantly modified lipids. In addition, cefepime treatment caused obvious alteration in the lipid-enriched membrane structure, neurites, mitochondria, and synaptic vesicles of primary cultured striatal neurons; moreover, the spontaneous electrical activity of striatal neurons was significantly reduced. Collectively, cefepime reprograms glycerophospholipid metabolism in the corpus striatum, which may interfere with neuronal structure and activity, eventually leading to aberrant neurobehaviors in mice.