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摘要: Melatonin (MLT) is a circadian hormone that reportedly influences the development and cyclic growth of secondary hair follicles; however, the mechanism of regulation remains unknown. Here, we systematically investigated the role of MLT in hair regeneration using a hair depilation mouse model. We found that MLT supplementation significantly promoted hair regeneration in the hair depilation mouse model, whereas supplementation of MLT receptor antagonist luzindole significantly suppressed hair regeneration. By analysing gene expression dynamics between the MLT group and luzindole-treated groups, we revealed that MLT supplementation significantly up-regulated Wnt/beta-catenin signalling pathway-related genes. In-depth analysis of the expression of key molecules in the Wnt/beta-catenin signalling pathway revealed that MLT up-regulated the Wnt/beta-catenin signalling pathway in dermal papillae (DP), whereas these effects were facilitated through mediating Wnt ligand expression levels in the hair follicle stem cells (HFSCs). Using a DP-HFSCs co-culture system, we verified that MLT activated Wnt/beta-catenin signalling in DPs when co-cultured with HFSCs, whereas supplementation of DP cells with MLT alone failed to activate Wnt/beta-catenin signalling. In summary, our work identified a critical role for MLT in promoting hair regeneration and will have potential implications for future hair loss treatment in humans.

摘要: Neoantigen delivery using extracellular vesicles (EVs) has gained extensive interest in recent years. EVs derived from tumour cells or immune cells have been used to deliver tumour antigens or antitumor stimulation signals. However, potential DNA contamination from the host cell and the cost of large-scale EV production hinder their therapeutic applications in clinical settings. Here, we develop an antigen delivery platform for cancer vaccines from red blood cell-derived EVs (RBCEVs) targeting splenic DEC-205+ dendritic cells (DCs) to boost the antitumor effect. By loading ovalbumin (OVA) protein onto RBCEVs and delivering the protein to DCs, we were able to stimulate and present antigenic OVA peptide onto major histocompatibility complex (MHC) class I, subsequently priming activated antigen-reactive T cells. Importantly, targeted delivery of OVA using RBCEVs engineered with anti-DEC-205 antibody robustly enhanced antigen presentation of DCs and T cell activation. This platform is potentially useful for producing personalised cancer vaccines in clinical settings. Red blood cell-derived extracellular vesicles (RBCEVs) are loaded with protein antigen and are surface-modified with DEC205-targeting antibodies. The antigen-loaded, DEC205-targeting RBCEVs are taken up by dendritic cells and antigens are processed. Via DEC205-mediated endocytosis, the antigens are digested and presented on MHC class I, which, in turn, activate CD8+ T cells. This mode of action improves T cell proliferation and activation while providing targeting effect towards secondary lymphoid organs in mice. image

摘要: Adult stem cells (ASCs) are pluripotent cells with the capacity to self-renew and constantly replace lost cells due to physiological turnover or injury. Understanding the molecular mechanisms of the precise coordination of stem cell proliferation and proper cell fate decision is important to regeneration and organismal homeostasis. The planarian epidermis provides a highly tractable model to study ASC complex dynamic due to the distinct spatiotemporal differentiation stages during lineage development. Here, we identified the myosin regulatory light chain (MRLC) homologue in the Dugesia japonica transcriptome. We found high expression levels of MRLC in wound region during regeneration and also expressed in late epidermal progenitors as an essential regulator of the lineage from neoblasts to mature epidermal cells. We investigated the function of MRLC using in situ hybridization, real-time polymerase chain reaction and double fluorescent and uncovered the potential mechanism. Knockdown of MRLC leads to a remarkable increase in cell death, causes severe abnormalities during regeneration and homeostasis and eventually leads to animal death. The global decrease in epidermal cell in MRLC RNAi animals induces accelerated epidermal proliferation and differentiation. Additionally, we find that MRLC is co-expressed with cdc42 and acts cooperatively to control the epidermal lineage development by affecting cell death. Our results uncover an important role of MRLC, as an inhibitor of apoptosis, involves in epidermal development.

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摘要: 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.

摘要: SARS-CoV-2 infection and the resultant COVID-19 pneumonia cause significant damage to the airway and lung epithelium. This damage manifests as mucus hypersecretion, pulmonary inflammation and fibrosis, which often lead to long-term complications collectively referred to as long COVID or post-acute sequelae of COVID-19 (PASC). The airway epithelium, as the first line of defence against respiratory pathogens, depends on airway basal stem cells (BSCs) for regeneration. Alterations in BSCs are associated with impaired epithelial repair and may contribute to the respiratory complications observed in PASC. Given the critical role of BSCs in maintaining epithelial integrity, understanding their alterations in COVID-19 is essential for developing effective therapeutic strategies. This study investigates the intrinsic properties of BSCs derived from COVID-19 patients and evaluates the modulatory effects of mesenchymal stem cells (MSCs). Through a combination of functional assessments and transcriptomic profiling, we identified key phenotypic and molecular deviations in COVID-19 patient-derived BSCs, including goblet cell hyperplasia, inflammation and fibrosis, which may underlie their contribution to PASC. Notably, MSC co-culture significantly mitigated these adverse effects, potentially through modulation of the interferon signalling pathway. This is the first study to isolate BSCs from COVID-19 patients in the Chinese population and establish a COVID-19 BSC-based xenograft model. Our findings reveal critical insights into the role of BSCs in epithelial repair and their inflammatory alterations in COVID-19 pathology, with potential relevance to PASC and virus-induced respiratory sequelae. Additionally, our study highlights MSC-based therapies as a promising strategy to address respiratory sequelae and persistent symptoms.

摘要: This study aimed to clarify the role and mechanism of tetrahedral framework nucleic acids (tFNAs) in regulating M2 macrophages to reduce intestinal injury. An intestinal injury model was established by intraperitoneal injection of lipopolysaccharides (LPS) in mice to explore the alleviating effects of tFNAs on intestinal injury. Inflammatory factors were detected by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). The intestinal barrier and permeability were assessed using western blotting and immunohistochemistry. Macrophages in the gut were localised and quantified using immunofluorescence. Western blotting was used to investigate the role and mechanism of tFNAs in regulating macrophages and alleviating inflammation in the injured intestines. These results show that tFNAs attenuated sepsis-induced intestinal injury. tFNAs can also promote the intestinal barrier reconstruction and reduce intestinal permeability. In vivo, tFNAs accelerated the aggregation of M2 macrophages at an early stage of injury and reduced the number of M1 macrophages in the intestine. In addition, tFNAs enhanced the clearance ability of intestinal macrophages. They activated the signalling and transcription activating factor 1(STAT1) and cytokine signalling inhibitory factor 1/3 (SOCS1/3) pathways by increasing the expression of the phagocytic receptor Mertk. These findings indicated that tFNAs can alleviate sepsis-induced intestinal injury by regulating M2 macrophages, providing a new option for treating intestinal injury.

摘要: Cellular mechanotransduction is a complex physiological process that integrates alterations in the external environment with cellular behaviours. In recent years, the role of the nucleus in mechanotransduction has gathered increased attention. Our research investigated the involvement of lamin A/C, a component of the nuclear envelope, in the mechanotransduction of macrophages under compressive force. We discovered that hydrostatic compressive force induces heterochromatin formation, decreases SUN1/SUN2 levels, and transiently downregulates lamin A/C. Notably, downregulated lamin A/C increased nuclear permeability to yes-associated protein 1 (YAP1), thereby amplifying certain effects of force, such as inflammation induction and proliferation inhibition. Additionally, lamin A/C deficiency detached the linker of nucleoskeleton and cytoskeleton (LINC) complex from nuclear envelope, consequently reducing force-induced DNA damage and IRF4 expression. In summary, lamin A/C exerted dual effects on macrophage responses to mechanical compression, promoting certain outcomes while inhibiting others. It operated through two distinct mechanisms: enhancing nuclear permeability and impairing intracellular mechanotransmission. The results of this study support the understanding of the mechanisms of intracellular mechanotransduction and may assist in identifying potential therapeutic targets for mechanotransduction-related diseases.

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