Isoliquiritigenin ameliorates abnormal oligodendrocyte development and behavior disorders induced by white matter injury.

Background: White matter injury is a predominant form of brain injury in preterm infants. However, effective drugs for its treatment are currently lacking. Previous studies have shown the neuroprotective effects of Isoliquiritigenin (ISL), but its impact on white matter injury in preterm infants remains poorly understood. Aims: This study aimed to investigate the protective effects of ISL against white matter injury caused by infection in preterm infants using a mouse model of lipopolysaccharide-induced white matter injury, integrating network pharmacology as well as in vivo and in vitro experiments. Methods: This study explores the potential mechanisms of ISL on white matter injury by integrating network pharmacology. Core pathways and biological processes affected by ISL were verified through experiments, and motor coordination, anxiety-like, and depression-like behaviors of mice were evaluated using behavioral experiments. White matter injury was observed using hematoxylin-eosin staining, Luxol Fast Blue staining, and electron microscopy. The development of oligodendrocytes and the activation of microglia in mice were assessed by immunofluorescence. The expression of related proteins was detected by Western blot. Results: We constructed a drug-target network, including 336 targets associated with ISL treatment of white matter injury. The biological process of ISL treatment of white matter injury mainly involves microglial inflammation regulation and myelination. Our findings revealed that ISL reduced early nerve reflex barriers and white matter manifestations in mice, leading to decreased activation of microglia and release of proinflammatory cytokines. Additionally, ISL demonstrated the ability to mitigate impairment in oligodendrocyte development and myelination, ultimately improving behavior disorders in adult mice. Mechanistically, we observed that ISL downregulated HDAC3 expression, promoted histone acetylation, enhanced the expression of H3K27ac, and regulated oligodendrocyte pro-differentiation factors. Conclusion: These findings suggest that ISL can have beneficial effects on white matter injury in preterm infants by alleviating inflammation and promoting oligodendrocyte differentiation.

SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1.

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy.

Microglial PCGF1 alleviates neuroinflammation associated depressive behavior in adolescent mice.

Epigenetics plays a crucial role in regulating gene expression during adolescent brain maturation. In adolescents with depression, microglia-mediated chronic neuroinflammation may contribute to the activation of cellular signaling cascades and cause central synapse loss. However, the exact mechanisms underlying the epigenetic regulation of neuroinflammation leading to adolescent depression remain unclear. In this study, we found that the expression of polycomb group 1 (PCGF1), an important epigenetic regulator, was decreased both in the plasma of adolescent major depressive disorder (MDD) patients and in the microglia of adolescent mice in a mouse model of depression. We demonstrated that PCGF1 alleviates neuroinflammation mediated by microglia in vivo and in vitro, reducing neuronal damage and improving depression-like behavior in adolescent mice. Mechanistically, PCGF1 inhibits the transcription of MMP10 by upregulating RING1B/H2AK119ub and EZH2/H3K27me3 in the MMP10 promoter region, specifically inhibiting microglia-mediated neuroinflammation. These results provide valuable insights into the pathogenesis of adolescent depression, highlighting potential links between histone modifications, neuroinflammation and nerve damage. Potential mechanisms of microglial PCGF1 regulates depression-like behavior in adolescent mice. Microglial PCGF1 inhibits NF-κB/MAPK pathway activation through regulation of RING1B/H2AK119ub and EZH2/H3K27me3 in the MMP10 promoter region, which attenuates neuroinflammation and ameliorates depression-like behaviors in adolescent mice.

Wrapping stem cells with wireless electrical nanopatches for traumatic brain injury therapy.

Electrical stimulation holds promise for enhancing neuronal differentiation of neural stem cells to treat traumatic brain injury. However, once the stem cells leave the stimulating material and migrate post transplantation, electrical stimulation on them is diminished. Here, we wrap the stem cells with wireless electrical nanopatches, the conductive graphene nanosheets. Under electromagnetic induction, electrical stimulation can thus be applied in-situ to individual nanopatch-wrapped stem cells on demand, stimulating their neuronal differentiation through a MAPK/ERK signaling pathway. Consequently, 41% of the nanopatch-wrapped stem cells differentiate into functional neurons in 5 days, as opposed to only 16.3% of the unwrapped ones. The brain injury male mice implanted with the nanopatch-wrapped stem cells and exposed to a rotating magnetic field 30 min/day exhibit significant recovery of brain tissues, behaviors, and cognitions, within 28 days. This study opens up an avenue to individualized electrical stimulation of transplanted stem cells for treating neurodegenerative diseases.

Therapeutic Effects of PEG-Modified Polyamide Amine Dendrimer for Cell Free DNA Adsorption in Temporomandibular Joint Osteoarthritis.

Temporomandibular joint osteoarthritis (TMJ OA) is characterized by the degeneration of cartilage and subchondral bone. In this study, we observed a significant increase in cell-free DNA (cfDNA) levels during the progression of TMJ OA. Bioinformatics analysis identified TLR9 as a pivotal molecule in TMJ OA pathogenesis. The polyamidoamine (PAMAM) dendrimer characterized by a well-structured, highly branched, and reactive nature, exhibits robust binding and clearance capabilities for cfDNA. However, the abundant amino groups on the surface of PAMAM lead to its inherent toxicity. To mitigate this, PEG-5000 was conjugated to the surface of PAMAM dendrimers, enhancing safety. Our results indicate that PEG-PAMAM effectively inhibits the upregulation of the TLR9 protein in TMJ OA, significantly suppressing the activation of the p-IκBα/p-NF-κB signaling pathway and subsequently decreasing chondrocyte inflammation and apoptosis, as evidenced by both in vivo and in vitro experiments. We conclude that PEG-PAMAM is a safe and effective material for in vivo applications, offering a promising therapeutic strategy for TMJ OA by targeting cfDNA clearance.

Multi-domain interaction mediated strength-building in human α-actinin dimers unveiled by direct single-molecule quantification.

α-Actinins play crucial roles in cytoskeletal mechanobiology by acting as force-bearing structural modules that orchestrate and sustain the cytoskeletal framework, serving as pivotal hubs for diverse mechanosensing proteins. The mechanical stability of α-actinin dimer, a determinant of its functional state, remains largely unexplored. Here, we directly quantify the force-dependent lifetimes of homo- and hetero-dimers of human α-actinins, revealing an ultra-high mechanical stability of the dimers associated with > 100 seconds lifetime within 40 pN forces under shear-stretching geometry. Intriguingly, we uncover that the strong dimer stability is arisen from much weaker sub-domain pair interactions, suggesting the existence of distinct dimerized functional states of the dimer, spanning a spectrum of mechanical stability, with the spectrin repeats (SRs) in folded or unfolded conformation. In essence, our study supports a potent mechanism for building strength in biomolecular dimers through weak, multiple sub-domain interactions, and illuminates multifaceted roles of α-actinin dimers in cytoskeletal mechanics and mechanotransduction.

RSDNet: A New Multiscale Rail Surface Defect Detection Model.

The rapid and accurate identification of rail surface defects is critical to the maintenance and operational safety of the rail. For the problems of large-scale differences in rail surface defects and many small-scale defects, this paper proposes a rail surface defect detection algorithm, RSDNet (Rail Surface Defect Detection Net), with YOLOv8n as the baseline model. Firstly, the CDConv (Cascade Dilated Convolution) module is designed to realize multi-scale convolution by cascading the cavity convolution with different cavity rates. The CDConv is embedded into the backbone network to gather earlier defect local characteristics and contextual data. Secondly, the feature fusion method of Head is optimized based on BiFPN (Bi-directional Feature Pyramids Network) to fuse more layers of feature information and improve the utilization of original information. Finally, the EMA (Efficient Multi-Scale Attention) attention module is introduced to enhance the network's attention to defect information. The experiments are conducted on the RSDDs dataset, and the experimental results show that the RSDNet algorithm achieves a mAP of 95.4% for rail surface defect detection, which is 4.6% higher than the original YOLOv8n. This study provides an effective technical means for rail surface defect detection that has certain engineering applications.

Melatonin improves mouse oocyte quality from 2-ethylhexyl diphenyl phosphate-induced toxicity by enhancing mitochondrial function.

2-Ethylhexyl diphenyl phosphate (EHDPP) is a representative organophosphorus flame retardant (OPFR) that has garnered attention due to its widespread use and potential adverse effects. EHDPP exhibits cytotoxicity, genotoxicity, developmental toxicity, and endocrine disruption. However, the toxicity of EHDPP in mammalian oocytes and the underlying mechanisms remain poorly understood. Melatonin is a natural free radical scavenger that has demonstrated cytoprotective properties. In this study, we investigated the effect of EHDPP on mouse oocytes in vitro culture system and evaluated the rescue effect of melatonin on oocytes exposed to EHDPP. Our results indicated that EHDPP disrupted oocyte maturation, resulting in the majority of oocytes arrested at the metaphase I (MI) stage, accompanied by cytoskeletal damage and elevated levels of reactive oxygen species (ROS). Nevertheless, melatonin supplementation partially rescued EHDPP-induced mouse oocyte maturation impairment. Results of single-cell RNA sequencing (scRNA-seq) analysis elucidated potential mechanisms underlying these protective effects. According to the results of scRNA-seq, we conducted further tests and found that EHDPP primarily disrupts mitochondrial distribution and function, kinetochore-microtubule (K-MT) attachment, DNA damage, apoptosis, and histone modification, which were rescued upon the supplementation of melatonin. This study reveals the mechanisms of EHDPP on female reproduction and indicates the efficacy of melatonin as a therapeutic intervention for EHDPP-induced defects in mouse oocytes.

SpRY-mediated screens facilitate functional dissection of non-coding sequences at single-base resolution.

CRISPR mutagenesis screens conducted with SpCas9 and other nucleases have identified certain cis-regulatory elements and genetic variants but at a limited resolution due to the absence of protospacer adjacent motif (PAM) sequences. Here, leveraging the broad targeting scope of the near-PAMless SpRY variant, we have demonstrated that saturated SpRY mutagenesis and base editing screens can faithfully identify functional regulatory elements and essential genetic variants for target gene expression at single-base resolution. We further extended this methodology to investigate a genome-wide association study (GWAS) locus at 10q22.1 associated with a red blood cell trait, where we identified potential enhancers regulating HK1 gene expression, despite not all of these enhancers exhibiting typical chromatin signatures. More importantly, our saturated base editing screens pinpoint multiple causal variants within this locus that would otherwise be missed by Bayesian statistical fine-mapping. Our approach is generally applicable to functional interrogation of all non-coding genomic elements while complementing other high-coverage CRISPR screens.

High-intensity interval training ameliorates postnatal immune activation-induced mood disorders through KDM6B-regulated glial activation.

Postnatal immune activation (PIA) induces persistent glial activation in the brain and causes various neuropathologies in adults. Exercise training improves stress-related mood disorders; however, the role of exercise in psychiatric disorders induced by early-life immune activation and the association between exercise training and glial activation remain unclear. We compared the effects of different exercise intensities on the PIA model, including high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). Both HIIT and MICT in adolescent mice inhibited neuroinflammation, remodeled synaptic plasticity, and improved PIA-induced mood disorders in adulthood. Importantly, HIIT was superior to MICT in terms of reducing inflammation and increasing body weight. RNA-seq of prefrontal cortex (PFC) tissues revealed a gene expression pattern, confirming that HIIT was more effective than MICT in improving brain glial cell activation through epigenetic modifications of KDM6B. We investigated the role of KDM6B, a specific histone lysine demethylation enzyme - histone 3 lysine 27 demethylase, in inhibiting glial activation against PIA-induced depression and anxiety by regulating the expression of IL-4 and brain-derived neurotrophic factor (BDNF). Overall, our data support the idea that HIIT improves PIA-induced mood disorders by regulating KDM6B-mediated epigenetic mechanisms and indicate that HIIT might be superior to MICT in improving mood disorders with PIA in mice. Our findings provide new insights into the treatment of anxiety and depression disorders.