摘要: Early fluctuations in blood glucose levels increased susceptibility to macrophage dysfunction. However, the underlying pathological mechanisms linking glucose variations and macrophage dysregulation remains elusive. In current study, we established an animal model of transient intermittent hyperglycaemia (TIH) to simulate early fluctuations in blood glucose levels. Our findings revealed that both TIH and diabetic group exhibited more severe periodontal lesions and increased secretion of pro-inflammatory cytokines compared to healthy controls. In immortalized bone marrow-derived macrophages (iBMDMs), phagocytosis and chemotaxis were impaired with transient and lasting hyperglycaemia, accompanied by enhanced glycolysis. We also found that TIH activated pyruvate kinase M2 (PKM2) through the phosphorylation of extracellular regulated protein kinase (ERK) in vivo, particularly at dimeric levels. In macrophage cultured with TIH, PKM2 translocated into the nucleus and involved in the regulating inflammatory genes, including TNF-alpha, IL-6 and IL-1 beta. PKM2 translocation and secretion of inflammatory cytokines were attenuated by PD98059, while PKM2 tetramer activator TEPP-46 prevented the formation of dimeric PKM2 in macrophages. Moreover, inhibition of glycolysis alleviated the TIH-induced pro-inflammatory cytokines. In conclusion, our manuscript provides a rationale for understanding how TIH modulates metabolic rewiring and dysfunction in macrophages via ERK-dependent PKM2 nuclear translocation. Glucose variation initiated ERK-dependent PKM2 nuclear translocation, leading to enhanced aerobic glycolysis and macrophages dysregulation. Our findings indicate that PKM2 represents a potential therapeutic target for immune-metabolism in inflammation. image

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摘要: A major risk factor for glaucoma, the first leading cause of irreversible blindness worldwide, is the decellularisation of the trabecular meshwork (TM) in the conventional outflow pathway. Stem cell-based therapy, particularly the utilisation of induced pluripotent stem cells (iPSCs), presents an enticing potential for tissue regeneration and intraocular pressure (IOP) maintenance in glaucoma. We have previously observed that differentiated iPSCs can stimulate endogenous cell proliferation in the TM, a pivotal factor in TM regeneration and aqueous humour outflow restoration. In this study, we investigated the response of TM cells in vivo after interacting with iPSC-derived cells and identified two subpopulations responsible for this relatively long-term tissue regeneration: ATP Binding Cassette Subfamily G Member 2 (ABCG2)-positive cells and Nestin (NES)-positive cells. We further uncovered that alterations of these responsive cells are linked to ageing and different glaucoma etiologies, suggesting that ABCG2(+) subpopulation decellularization could serve as a potential risk factor for TM decellularization in glaucoma. Taken together, our findings illustrated the proliferative subpopulations in the conventional outflow pathway when stimulated with iPSC-derived cells and defined them as TM precursors, which may be applied to develop novel therapeutic approaches for glaucoma.

摘要: In non-small cell lung cancer (NSCLC), metastasis is the most common phenotype, and autophagy plays a vital role in its regulation. However, there are limited data on how autophagy-related genes and metastasis-related genes affect NSCLC progression. Our goal was to identify the genes that regulate autophagy and metastasis in NSCLC, and to assess the underlying mechanisms in this current study. RNA sequencing data from public databases were used to screen differentially expressed autophagy- and metastasis-associated genes. Enrichment analyses and immune correlations were conducted to identify hub genes and potential regulating pathways in NSCLC. In this study, we found that CCL2 expression was highly expressed in NSCLC tissues and high CCL2 level was correlated with strong infiltration in lung tissues from NSCLC patients. Overexpression of CCL2 can enhance the metastasis of NSCLC cells in nude mice. Furthermore, CCL2 activated the PI3K/Akt/mTOR signalling pathway axis, promoted epithelial-mesenchymal transition (EMT), and blocked the autophagic flux in NSCLC cells. Therefore, our results indicate that CCL2 promotes metastasis and EMT of NSCLC via PI3K/Akt/mTOR axis and autophagy signalling pathways. We believe that CCL2 could be a probable target for the diagnosis and therapeutics of NSCLC, and this study may expand our understanding of lung cancer.

摘要: Enteric glial cells in the enteric nervous system are critical for the regulation of gastrointestinal homeostasis. Increasing evidence suggests two-way communication between enteric glial cells and both enteric neurons and immune cells. These interactions may be important in the pathogenesis of Crohn's disease (CD), a chronic relapsing disease characterized by a dysregulated immune response. Structural abnormalities in glial cells have been identified in CD. Furthermore, classical inflammatory pathways associated with CD (e.g., the nuclear factor kappa-B pathway) function in enteric glial cells. However, the specific mechanisms by which enteric glial cells contribute to CD have not been summarized in detail. In this review, we describe the possible roles of enteric glial cells in the pathogenesis of CD, including the roles of glia-immune interactions, neuronal modulation, neural plasticity, and barrier integrity. Additionally, the implications for the development of therapeutic strategies for CD based on enteric glial cell-mediated pathogenic processes are discussed.

摘要: Dental pulp injury remains a clinical challenge with limited therapeutic approaches. In the present study, we sought to prove that dental pulp stromal cells (DPSCs) mitochondrial transfer could promote dental pulp injury repair and endoplasmic reticulum (ER)-mitochondrial contacts have a significant regulatory effect on mitochondrial transfer. Healthy DPSCs were co-cultured directly or indirectly with injured DPSCs in the first molar of 1-2 month SD rats or in vitro. Mitochondrial transfer was observed after 24 h of co-culture using fluorescence microscopy and live cell workstation. After co-culture for 1W, 8-OhdG immunofluorescence, mitochondrial membrane potential and total oxidant status/total antioxidant status were used to detect the mitochondrial function of injured DPSCs before and after mitochondrial transfer. Subsequently, mitochondria-ER co-transfer was regulated by modulating mitochondria-ER binding in healthy DPSCs, and the results of GRP78 and CHOP in DPSCs, and PDI immunofluorescence and haematoxylin and eosin staining of pulp tissue were analysed to clarify the effects of modulating mitochondria-ER co-transfer on endoplasmic reticulum stress (ERS), and on pulp injury repair. Fluorescence microscopy and live cell workstation results showed significant mitochondrial transfer between DPSCs. Meanwhile, mitochondrial transfer significantly restored mitochondrial function in injured DPSCs. By modulating mitochondrial-ER binding, the efficiency of mitochondrial transfer between DPSCs was significantly affected and had an impact on ERS in injured cells. Mitochondrial transfer of DPSCs significantly promotes pulpal injury repair and functional recovery of damaged DPSCs, and mitochondrial transfer of DPSCs is regulated by mitochondria-ER binding.

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摘要: Osteoarthritis (OA) is the most prevalent degenerative joint disease worldwide, imposing a substantial global disease burden. However, its pathogenesis remains incompletely understood, and effective treatment strategies are still lacking. Organoid technology, in which stem cells or progenitor cells self-organise into miniature tissue structures under three-dimensional (3D) culture conditions, provides a promising in vitro platform for simulating the pathological microenvironment of OA. This approach can be employed to investigate disease mechanisms, carry out high-throughput drug screening and facilitate personalised therapies. This review summarises joint structure, OA pathogenesis and pathological manifestations, thereby establishing the disease context for the application of organoid technology. It then examines the components of the arthrosis organoid system, specifically addressing cartilage, subchondral bone, synovium, skeletal muscle and ligament organoids. Furthermore, it details various strategies for constructing OA organoids, including considerations of cell selection, pathological classification and fabrication techniques. Notably, this review introduces the concept of intelligent manufacturing of OA organoids by incorporating emerging engineering technologies such as artificial intelligence (AI) into the organoid fabrication process, thereby forming an innovative software and hardware cluster. Lastly, this review discusses the challenges currently facing intelligent OA organoid manufacturing and highlights future directions for this rapidly evolving field. By offering a comprehensive overview of state-of-the-art methodologies and challenges, this review anticipates that intelligent, automated fabrication of OA organoids will expedite fundamental research, drug discovery and personalised translational applications in the orthopaedic field.

摘要: Hepatic ischemia-reperfusion injury (HIRI) substantially influences the prognosis of liver transplant recipients. Although kynurenic acid (KYNA) has been associated with protective effects against ischemia-reperfusion injury in various organs, the precise mechanisms underlying its protective role in HIRI are not well elucidated. In this study, a 70% mouse HIRI model and an in vitro hypoxia/reoxygenation model were employed to examine the protective effects of KYNA on HIRI. In this study, we illustrate that KYNA influences the methylation status of the Hippo signalling pathway by enhancing the expression of the fat mass and obesity-associated gene (FTO). Within this pathway, large tumour suppressor kinase 1 (LATS1) is identified as a direct target of FTO. Moreover, the stability of LATS1 mRNA exhibits an inverse correlation with FTO levels and is modulated through its interaction with YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2). The reduction in LATS1 expression facilitated Yes-associated protein (YAP) nuclear translocation, decreased hepatocyte apoptosis, and mitigated HIRI. Clinically, elevated levels of serum KYNA correlate with a diminished severity of liver injury post-transplantation. our work revealed that KYNA possesses significant clinical translational potential for the prevention of HIRI, and further exploration of its underlying mechanisms was conducted.

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