In spite of great advances in modern medicine, there are a few effective strategies for the treatment of neurodegenerative diseases characterised by neuron loss or degeneration. This results from complex pathogenesis of the diseases and the limited drug uptake of the brain due to the presence of blood-brain barrier. Nanoparticle-based drug delivery systems are expected to improve the drug utilisation. Polymeric nanoparticles represent promising drug delivery carriers to the brain due to their unique advantages such as good biodegradability and biocompatibility, flexibility in surface modification and nontoxicity. In addition, the delivery of genetic drugs may stop the progression of neurodegenerative diseases at the genetic level and even avoid the irreversible damage in the central nervous system. In this review, an overview of studies on polymer-based nanoparticles for drug delivery to the central nervous system in typical neurodegenerative diseases, especially Alzheimer's diseases and Parkinson's diseases, is described. Meanwhile, their applications in gene delivery in these disorders are discussed. And the challenges and future perspectives for the development of polymeric nanoparticles as drug delivery carriers in neurodegenerative diseases are concluded.

Immune rejection is a major barrier to the successful human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) transplantation for age-related macular degeneration (AMD). Traditional strategies to mitigate immune rejection involve ablating major histocompatibility complex (MHC) molecules on hESC-RPE. An alternative approach is immune checkpoint overexpression, avoiding natural killer (NK) cell-mediated destruction due to MHC-I deficiency. Our study highlights the benefits of PD-L1 overexpression without requiring MHC gene deletion, which preserved the immunosuppressive functions of hESC-RPE on NK cells. In Vivo experiments in retinal degeneration models showed that PD-L1-expressing hESC-RPE grafts exhibited significantly higher survival, reduced apoptosis and enhanced visual protection. Single-cell transcriptomics revealed reduced immune activation and oxidative stress in PD-L1-overexpressing grafts. PD-L1's protective role was further evidenced by improved light transduction in host photoreceptors. These findings support PD-L1 overexpression as a promising strategy to improve the efficiency of hESC-RPE-based therapy for AMD.

Livestock pluripotent stem cells, derived either from early embryos or induced through somatic cell reprogramming technology, possess the unique ability to self-renew, maintain an undifferentiated state and differentiate into various cell types. Consequently, the generation of PSCs from agricultural animal species holds great potential for applications in livestock breed improvement, rapid propagation, disease modelling and xenotransplantation. However, compared to the great achievements made in mouse and human pluripotent stem cells research, the generation of livestock pluripotent stem cells still remains challenging. This article offers an overview of the classification, regulatory mechanisms of pluripotency, and developmental history of livestock pluripotent stem cells, while also anticipating their future application prospects. These insights provide valuable references for the reproduction and breeding of large livestock.

Neutrophil extracellular traps (NETs) act as a vital first line of defence against tissue damage and pathogens, playing a significant role in improving diseases such as intestinal ischemia reperfusion injury (IRI). However, we observed that after intestinal injury, intestinal bacteria and lipopolysaccharides (LPS) can enter the circulatory system, leading to a significant secondary increase in NETs production and the subsequent activation of a coagulation cascade. This phenomenon contributes to a pathological process known as the ‘second strike’ of NETs, which exaggerates intestinal damage and microcirculation disturbance. Selectively mitigating the detrimental effects associated with this second strike presents a promising therapeutic strategy. We developed an innovative conjugate of stroke-homing peptide (SHp) and DNase1 (SHp-DNase1) to enhance the stability of DNase in the bloodstream while selectively targeting NETs in thromboembolic events. The effects of SHp-DNase1 on blood flow, ischemia, and vascular leakage were evaluated in a mouse model using laser Doppler flowmetry and an in vivo imaging system. Levels of LPS and NETs were elevated in patients with IRI. Similarly, the expression of NETs and LPS was upregulated in mice with intestinal IRI. In vivo imaging revealed disturbances in intestinal microcirculation, accompanied by intestinal leakage, which were effectively reversed by the administration of SHp-DNase1. Almost all of the SHp-DNase1 localised to the gastrointestinal tract, demonstrating the effective targeting of DNase1 to the site of intestinal injury via SHp guidance. Furthermore, the combination of SHp-DNase1 and CRO significantly reduced the expression of ischemia-inducible factors, leading to a marked decrease in mortality in the mouse model. These findings suggest that intestinal LPS leakage correlated with NETs exacerbation plays a critical role in IRI. The combination of SHp-DNase1 and CRO is an effective treatment strategy by simultaneously controlling inflammation and addressing microcirculatory disorders induced by NETs in the therapy of IRI.

Exploring effective, prompt and universally applicable approaches for inducing the differentiation of glioblastoma (GBM) into terminally differentiated cells, such as astrocytes or neurons that cease cell division, is pivotal for the success of GBM differentiation therapy. In this study, a neuronal-specific promoter–reporter system was employed to screen small molecules that promote neural differentiation. The cocktail YFSS, consisting of Y27632, Forskolin, SB431542 and SP600125, which selectively targets the ROCK, cAMP, TGF-β and JNK signalling pathways, respectively, was found to effectively trigger differentiation in human GBM cells. This process yielded neuron-like cells within 7 days, inhibited GBM cell proliferation and reduced malignancy traits, such as stemness, migratory and invasive capabilities. Transcriptome sequencing revealed the pathways altered by YFSS, shedding light on its dual role in halting cell proliferation and initiating neuronal differentiation. A notable increase in CEND1 expression, a key molecule in cell cycle and neuronal differentiation regulation, was observed during differentiation. However, CEND1 alone could not replicate YFSS's high conversion efficiency and its depletion reduced the differentiation and restored proliferation of the GBM cells. In vivo, prolonged and localised YFSS application significantly curtailed tumour growth and extended survival in patient-derived xenograft mice models. In summary, our findings reveal that the small-molecule cocktail YFSS is an effective means for inducing neuronal differentiation in GBM cells, representing a novel and promising pathway for the advancement of GBM treatment.

Maternal age has been reported to impair oocyte quality. However, the molecular mechanisms underlying the age-related decrease in oocyte competence remain poorly understood. Cumulus cells establish direct contact with the oocyte through gap junctions, facilitating the provision of crucial nutrients necessary for oocyte development. In this study, we obtained the proteomic and metabolomic profiles of cumulus cells from both young and old mice. We found that fatty acid beta-oxidation and nucleotide metabolism, markedly active in aged cumulus cells, may serve as a compensatory mechanism for energy provision. Tryptophan undergoes two principal metabolic pathways, including the serotonin (5-HT) synthesis and kynurenine catabolism. Notably, we discovered that kynurenine catabolism is reduced in aged cumulus cells compared to young cells, whereas 5-HT synthesis exhibited a significant decrease. Furthermore, the supplement of 5-HT during cumulus-oocyte complexes (COCs) culture significantly ameliorated the metabolic dysfunction and meiotic defects in old oocytes. In sum, our data provide a comprehensive multiple omics resource, offering potential insights for improving oocyte quality and promoting fertility in aged females.

Astrocytes are crucial for central nervous system (CNS) development and function, with their differentiation being stringently controlled by epigenetic mechanisms, such as histone modifications. Enhancer of Zeste Homologue 2 (EZH2), a histone methyltransferase, is essential for the suppression of gene expression. However, the role of EZH2 in astrocyte early morphogenesis has remained unclear. Using an astrocyte-specific Ezh2 knockout (cKO) mouse model, we examined the effects of EZH2 deletion on astrocyte morphogenesis, blood–brain barrier (BBB) integrity and neurodevelopment. Loss of EZH2 led to increased glial fibrillary acidic protein (GFAP) expression, altered astrocyte morphology and reduced coverage of astrocytic endfeet on blood vessels, compromising BBB integrity. Vascular abnormalities, characterised by increased vascular density and smaller vessel diameter, mirrored compensatory changes seen in moyamoya disease. RNA-sequencing and ChIP-seq identified Ddn as a key upregulated gene in Ezh2^cKO astrocytes, influencing cytoskeletal changes via the MAPK/ERK pathway. Behavioural analysis revealed autism-like traits, such as reduced vocalisations, without significant anxiety-like behaviour. These findings highlight EZH2 as a critical regulator of astrocyte function, with its disruption contributing to neurodevelopmental disorders. This study provides novel insights into the molecular pathways governing astrocyte differentiation and suggests EZH2 as a promising therapeutic target for gliomas and other CNS disorders.

Copper deficiency, commonly observed in myocardial infarction, leads to cardiomyocyte loss and cardiac dysfunction, yet the mechanism driving copper efflux remains unclear. To further elucidate the relationship between copper transporters and cardiac copper efflux during chronic myocardial ischemia, a rhesus monkey model was established by performing the permanent ligation of the left anterior descending coronary artery. A dramatic decrease in copper concentration within ischemic cardiomyocytes was observed alongside declining cardiac function. Among major copper transporters, COMMD1 and ATP7B were significantly upregulated in the ischemic myocardium. COMMD1 was specifically localised in cardiomyocytes undergoing copper efflux, whereas increased ATP7B was restricted to cardiac fibroblasts. This indicates that elevated COMMD1 regulates copper efflux in cardiomyocytes during chronic myocardial ischemia, functioning independently of its interactions with P-type ATPase transporters. Given the discrepancy between RNA and protein levels of COMMD1 in ischemic myocardium, post-translational modification is likely responsible for regulating COMMD1 expression. We found that the copper-binding protein with E3 ubiquitin ligase activity, XIAP, augmented before the rise in COMMD1 expression within ischemic cardiomyocytes. Excessive XIAP specifically interacted with COMMD1 to enhance its protein levels under copper-deprivation conditions and vice versa. Overall, our findings reveal a positive feedback loop among XIAP, COMMD1 and copper, highlighting the intricate interplay between XIAP and COMMD1 in regulating copper efflux in cardiomyocytes. This loop sets the stage for further investigation into therapeutic strategies to manage copper homeostasis in chronic myocardial ischemia.

The cell cycle is crucial for maintaining normal cellular functions and preventing replication errors. FOXM1, a key transcription factor, plays a pivotal role in regulating cell cycle progression and is implicated in various physiological and pathological processes, including cancers like liver, prostate, breast, lung and colon cancer. Despite previous research, our understanding of FOXM1 dynamics under different cell cycle perturbations and its connection to heterogeneous cell fate decisions remains limited. In this study, we investigated FOXM1 behaviour in individual cells exposed to various perturbagens. We found that different drugs induce diverse responses due to heterogeneous FOXM1 dynamics at the single-cell level. Single-cell analysis identified six distinct cellular phenotypes: on-time cytokinesis, cytokinesis delay, cell cycle delay, G1 arrest, G2 arrest and cell death, observed across different drug types and doses. Specifically, treatments with PLK1, CDK1, CDK1/2 and Aurora kinase inhibitors revealed varied FOXM1 dynamics leading to heterogeneous cellular outcomes. Our findings affirm that the dynamics of FOXM1 are essential in shaping cellular outcomes, influencing the signals that dictate responses to various stimuli. Our results gave insights into how FOXM1 dynamics contribute to cell cycle fate decisions, especially under different cell cycle perturbations.

Human periodontal ligament stem cells (hPDLSCs) have emerged as promising candidates for the treatment of osteoporotic bone defects. Previous studies have indicated that m⁶A plays a crucial role in regulating the osteogenic differentiation of hPDLSCs. However, research on the relationship between YTHDC1, as a reading protein, and the osteogenic differentiation of hPDLSCs remains unexplored. This study aimed to investigate the biological roles of YTHDC1 in the osteogenic differentiation of hPDLSCs and to explore underlying mechanisms. Dot blot analysis revealed a progressive increase in m⁶A methylation during osteogenic differentiation, accompanied by significant upregulation of YTHDC1 expression, as evidenced by qPCR and Western blot. Functional assays utilising siRNA-mediated knockdown and lentiviral-mediated overexpression demonstrated that YTHDC1 positively regulated the osteogenic differentiation potential of hPDLSCs. Mechanistically, mRNA-seq analysis implicated the Wnt/β-catenin signalling pathway, which was further validated through rescue experiments with the Wnt inhibitor DKK1. Notably, in vivo experiments showed that hPDLSCs overexpressing YTHDC1 exhibited enhanced bone formation capacity in the osteoporotic rats. In conclusion, our findings suggested that YTHDC1 modulated the osteogenic capacity of hPDLSCs through the Wnt/β-catenin signalling pathway, highlighting its therapeutic potential for treating bone defects in osteoporotic conditions.

Membraneless organelles (MLOs) are a type of subcellular compartment structure discovered in eukaryotes in recent years. They are mainly formed through the liquid–liquid phase separation (LLPS) and aggregation of macromolecular substances such as proteins or nucleic acids in cells. When cells are stimulated, they initiate a series of stress responses including gene transcription, RNA metabolism, translation, protein modification and signal transduction to maintain homeostasis. The dysregulation of these cellular processes is a key event in the occurrence and development of cancer. This article provides an overview of the structure and function of membraneless organelles, as well as the mechanisms of phase separation, to summarise the latest research progress on phase separation in tumours. It focuses on the role and molecular mechanism of LLPS in the development of tumours, with the aim of providing new theoretical references for developing drug action targets and innovative treatment strategies.

Mammalian olfactory epithelium (OE) undergoes consistent self-renewal throughout life. In OE homeostasis, globose basal cells (GBCs) contribute to the generation of olfactory sensory neurons (OSNs) to replace old ones. Chitinase-like 4 (Chil4), a chitinase-like protein expressed in supporting cells, plays a critical role in OE regeneration, while its role in tissue homeostasis is still elusive. Here, we found that Chil4 is upregulated in the aged OE. Deletion of Chil4 leads to a reduction in the number of GBCs and immature OSNs (iOSNs). Chil4^−/− GBCs show attenuation in cell cycle progression and an aberrant expression pattern of cell-cycle-related genes such as Cdk1. Chil4 deletion causes loss of a specific subcluster of GAP43⁺ iOSNs expressing Cebpb, Nqo1 and low level of mature OSN (mOSN) marker Stoml3 (iOSN_CeSt^LNq), potentially suggesting a transitional state between immature and mature neurons. Chil4 knockout induces inflammatory activation in Iba1⁺ microglia (MG)-like cells in the OE. Chil4 downregulation in aged organoids reduced the number of mature sensory neurons, suggesting a necessary role of Chil4 in maintaining neuronal generation in the aged OE. Collectively, these observations reveal a previously unidentified function of Chil4, establishing the cellular mechanism underlying OE homeostasis.