摘要: Targeting base excision repair (BER) has been an attractive strategy in cancer therapeutics. RNA-binding motif protein 39 (RBM39) modulates the alternative splicing of numerous genes involved in cancer occurrence and progression. However, whether and how RBM39 regulates BER in hepatocellular carcinoma (HCC) remain unclear. Here, we found that under oxidative stress, RBM39 degradation or knockdown decreased BER efficiency in HCC cells using a well-designed BER reporter. Further assays showed that RBM39 promoted HCC cell proliferation, migration, and invasion, enhancing cell survival and inhibiting apoptosis. Mechanistically, RBM39 interacted with the mRNA of the essential glycosidase 8-oxoguanine-DNA glycosylase 1 (OGG1), thereby stabilising OGG1 mRNA. This in turn increases OGG1 expression and promotes BER efficiency in HCC. Moreover, data suggested that RBM39 degradation, combined with oxidative damage, could be more effective for HCC treatment than monotherapy, both in vitro and in xenograft mice models. Overall, we demonstrated that RBM39 regulated OGG1 stabilisation and improved BER efficiency, suggesting that combining the RBM39 degradant indisulam with the oxidising agent KBrO3 could be an emerging strategy for HCC treatment.

摘要: Ageing is often accompanied by cognitive decline and an increased risk of dementia. Exercise is a powerful tool for slowing brain ageing and enhancing cognitive function, as well as alleviating depression, improving sleep, and promoting overall well-being. The connection between exercise and healthy brain ageing is particularly intriguing, with exercise-induced pathways playing key roles. This review explores the link between exercise and brain health, focusing on how skeletal muscle influences the brain through muscle-brain crosstalk. We examine the interaction between the brain with well-known myokines, including brain-derived neurotrophic factor, macrophage colony-stimulating factor, vascular endothelial growth factor and cathepsin B. Neuroinflammation accumulates in the ageing brain and leads to cognitive decline, impaired motor skills and increased susceptibility to neurodegenerative diseases. Finally, we examine the evidence on the effects of exercise on neuronal myelination in the central nervous system, a crucial factor in maintaining brain health throughout the lifespan.

摘要: T-cell acute lymphoblastic leukaemia (T-ALL) is a heterogeneous malignant disease with high relapse and mortality rates. To characterise the multiomics features of T-ALL, we conducted integrative analyses using single-cell RNA, TCR and chromatin accessibility sequencing on pre- and post-treatment peripheral blood and bone marrow samples of the same patients. We found that there is transcriptional rewiring of gene regulatory networks in T-ALL cells. Some transcription factors, such as TCF3 and KLF3, showed differences in activity and expression levels between T-ALL and normal T cells and were associated with the prognosis of T-ALL patients. Furthermore, we identified multiple malignant TCR clonotypes among the T-ALL cells, where the clonotypes consisted of distinct combinations of the same TCR alpha and beta chain per patient. The T-ALL cells displayed clonotype-specific immature thymocyte cellular characteristics and response to chemotherapy. Remarkably, T-ALL cells with an orphan TCR beta chain displayed the strongest stemness and resistance to chemotherapy. Our study provided transcriptome and epigenome characterisation of T-ALL cells categorised by TCR clonotypes, which may be helpful for the development of novel predictive markers to evaluate treatment effectiveness for T-ALL.

摘要: The progression of periodontitis, a bacteria-driven inflammatory and bone-destructive disease, involves myriad cellular and molecular mechanisms. Protein regulation significantly influences the pathogenesis and management of periodontitis. However, research regarding its regulatory role in periodontitis remains relatively limited. The ubiquitin-proteasome system (UPS), which mainly involves ubiquitination by E3 ubiquitin ligases (E3s) and deubiquitination by deubiquitinating enzymes (DUBs), is the primary intracellular and non-lysosomal mechanism of protein degradation. Recent studies have provided compelling evidence to support the involvement of UPS in periodontitis progression. Increasing evidence indicated that E3s, such as CUL3, Nedd4-2, Synoviolin, FBXL19, PDLIM2, TRIMs and TRAFs, modulate inflammatory responses and bone resorption in periodontitis through multiple classical signalling pathways, including NLRP3, GSDMD, NF-kappa B, Wnt/beta-catenin and Nrf2. Meanwhile, DUBs, including OTUD1, A20, CYLD, UCH-L1 and USPs, also broadly modulate periodontitis progression by regulating signalling pathways such as NF-kappa B, Wnt/beta-catenin, NLRP3, and BMP2. Therefore, the modulation of E3s and DUBs has proven to be an effective therapy against periodontitis. This review provides a comprehensive overview of the regulatory role of ubiquitinating and deubiquitinating enzymes in periodontitis progression and the underlying mechanisms. Finally, we summarise several chemical and genetic methods that regulate UPS enzymes and pave the way for the development of targeted therapies for periodontitis.

摘要: As crucial phagocytes of the innate immune system, macrophages (M phi s) protect mammalian hosts, maintain tissue homeostasis and influence disease pathogenesis. Nonetheless, M phi s are susceptible to various pathogens, including bacteria, viruses and parasites, which cause various infectious diseases, necessitating a deeper understanding of pathogen-M phi interactions and therapeutic insights. Pluripotent stem cells (PSCs) have been efficiently differentiated into PSC-derived M phi s (PSCdM phi s) resembling primary M phi s, advancing the modelling and cell therapy of infectious diseases. However, the mass production of PSCdM phi s, which lack proliferative capacity, relies on large-scale expansions of PSCs, thereby increasing both costs and culture cycles. Notably, M phi s deficient in the MafB/c-Maf genes have been reported to re-enter the cell cycle with the stimulation of specific growth factor cocktails, turning into self-renewing M phi s (SRM phi s). This review summarizes the applications of PSCdM phi s in the modelling and cell therapy of infectious diseases and strategies for establishing SRM phi s. Most importantly, we innovatively propose that PSCs can serve as a gene editing platform to creating PSC-derived SRM phi s (termed PSRM phi s), addressing the resistance of M phi s against genetic manipulation. We discuss the challenges and possible solutions in creating PSRM phi s. In conclusion, this review provides novel insights into the development of physiologically relevant and expandable M phi models, highlighting the enormous potential of PSRM phi s as a promising avenue for the modelling and cell therapy of infectious diseases.

摘要: Breast cancer is associated with high morbidity and mortality, which are closely influenced by protein post-translational modifications (PTMs). Lysine crotonylation (Kcr) serves as a newly identified PTM type that plays a role in various biological processes; however, its involvement in breast cancer progression remains unclear. Minichromosome maintenance 6 (MCM6) is a critical component of DNA replication and has been previous confirmed to exhibit a significant role in tumorigenesis. Despite this, a comprehensive analysis of MCM6, particularly regarding its modifications in breast cancer is lacking. In this study, we found MCM6 is upregulated in breast invasive carcinoma (BRCA) and is associated with poorer overall survival by regulating the DNA damage repair mechanisms. Furthermore, MCM6-knockdown resulted in decreased cell proliferation and inhibited the DNA replication, leading to DNA replication stress and sustained DNA damage, thereby enhancing the chemotherapeutic sensitivity of breast cancer. Additionally, SIRT7-mediated crotonylation of MCM6 at K599 (MCM6-K599cr) was significantly upregulated in response to DNA replication stress, primarily due to the disassemebly of the MCM2-7 complex and regulated by RNF8-mediated ubiquitination. Concurrently, kaempferol, which acts as a regulator of SIRT7, was found to enhance the Kcr level of MCM6, reducing tumour weight, particular when combined with paclitaxel, highlighting its potential chemotherapeutic target for BRCA therapy.

摘要: The coronavirus disease 2019 (COVID-19) pandemic increases the risk of adverse fetal outcomes during pregnancy. Maternal infection during pregnancy, particularly with cytomegalovirus (CMV), hepatitis B and C virus, and human immunodeficiency virus can have detrimental effects on both mother and fetus, potentially leading to adverse outcomes such as spontaneous abortion or neonatal infection. However, the impact of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection on the maternal-fetal interface remains poorly understood. In this study, we initially utilised immunofluorescence and immunohistochemical to investigate placental samples from pregnant women who were infected with SARS-CoV-2 during the first trimester. Our data indicate that infection in the first trimester induces an upregulation of hypoxia inducible factor (HIF) levels at the maternal-fetal interface. Subsequently, single-cell RNA sequencing and metabolomics sequencing analyses reveal alterations in maternal-fetal interface. Remarkably, immune cells exhibited low expression levels of HIF possibly associated with immune activation. Furthermore, our findings demonstrate a gradual reduction in transcriptome and metabolic changes as gestation progressed beyond 12-16 weeks compared to samples obtained at 6-8 weeks gestation. Overall, our study suggests that early-stage SARS-CoV-2 infection during the first trimester leads to severe hypoxia and aberrant cell metabolism at the maternal-fetal interface which gradually resolves as pregnancy progresses. Nevertheless, these abnormal changes may have long-term implications for maternal-fetal interface development.

摘要: Circular RNAs (circRNAs) are novel regulatory RNAs with high evolutionary conservation and stability, which makes them effective therapeutic agents for various vascular diseases. The SMAD family is a downstream mediator of the canonical transforming growth factor beta (TGF-beta) signalling pathway and has been considered as a critical regulator in vascular injury. However, the role of circRNAs derived from the SMAD family members in vascular physiology remains unclear. In this study, we initially identified potential functional circRNAs originating from the SMAD family using integrated transcriptome screening. circSMAD3, derived from the SMAD3 gene, was identified to be significantly downregulated in vascular injury and atherosclerosis. Transcriptome analysis was conducted to comprehensively illustrate the pathways modulated by circRNAs. Functionally, circSMAD3 repressed vascular smooth muscle cell (VSMC) proliferation and phenotype switching in vitro evidenced by morphological assays, and ameliorated arterial injury-induced neointima formation in vivo. Mechanistically, circSMAD3 interacted with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) within the nucleus, enhanced its interaction with E3 ligase WD repeat domain 76 to promote hnRNPA1 ubiquitination degradation, facilitated p53 pre-RNA splicing, activated the p53 gamma signalling pathway, and finally suppressed VSMC proliferation and phenotype switching. Our study identifies circSMAD3 as a novel epigenetic regulator that suppresses VSMC proliferation and phenotype switching, thereby attenuating vascular remodelling and providing a new circRNA-based therapeutic strategy for cardiovascular diseases.

摘要: Chronic allograft dysfunction (CAD) poses a significant challenge in kidney transplantation, with renal vascular endothelial-to-mesenchymal transition (EndMT) playing a vital role. While renal vascular EndMT has been verified as an important contributing factor to renal allograft interstitial fibrosis/tubular atrophy in CAD patients, its underlying mechanisms remain obscure. Currently, Src activation is closely linked to organ fibrosis development. Single-cell transcriptomic analysis in clinical patients revealed that Src is a potential pivotal mediator in CAD progression. Our findings revealed a significant upregulation of Src which closely associated with EndMT in CAD patients, allogeneic kidney transplanted rats and endothelial cells lines. In vivo, Src inhibition remarkably alleviate EndMT and renal allograft interstitial fibrosis in allogeneic kidney transplanted rats. It also had a similar antifibrotic effect in two endothelial cell lines. Mechanistically, the knockout of Src resulted in an augmented AMBRA1-mediated mitophagy in endothelial cells. We demonstrate that Src knockdown upregulates AMBRA1 level and activates mitophagy by stabilizing Parkin's ubiquitination levels and mitochondrial translocation. Subsequent experiments demonstrated that the knockdown of the Parkin gene inhibited mitophagy in endothelial cells, leading to increased production of Interleukin-6, thereby inducing EndMT. Consequently, our study underscores Src as a critical mediator of renal vascular EndMT and allograft interstitial fibrosis, exerting its impact through the regulation of AMBRA1/Parkin-mediated mitophagy.

摘要: The regulatory mechanisms involved in embryonic development are complex and yet remain unclear. SCP4 represents a novel nucleus-resident phosphatase identified in our previous study. The primary aim of this study was to elucidate the function of SCP4 in the progress of cartilage development and endochondral osteogenesis. SCP4(-/-) and SCP4Col2ER mice were constructed to assess differences in bone formation using whole skeleton staining. ABH/OG staining was used to compare chondrocyte differentiation and cartilage development. Relevant biological functions were analysed using RNA-sequencing and GO enrichment, further validated by immunohistochemical staining, Co-IP and Western Blot. Global SCP4 knockout led to abnormal embryonic development in SCP4(-/-) mice, along with delayed endochondral osteogenesis. In parallel, chondrocyte-specific removal of SCP4 yielded more severe embryonic deformities in SCP4(Col2ER) mice, including limb shortening, reduced chondrocyte number in the growth plate, disorganisation and cell enlargement. Moreover, RNA-sequencing analysis showed an association between SCP4 and chondrocyte apoptosis. Notably, Tunnel-positive cells were indeed increased in the growth plates of SCP4(Col2ER) mice. The deficiency of SCP4 up-regulated the expression levels of pro-apoptotic proteins both in vivo and in vitro. Additionally, phosphorylation of FoxO3a (pFoxO3a), a substrate of SCP4, was heightened in chondrocytes of SCP4(Col2ER) mice growth plate, and the direct interaction between SCP4 and pFoxO3a was further validated in chondrocytes. Our findings underscore the critical role of SCP4 in regulating cartilage development and endochondral osteogenesis during embryonic development partially via inhibition of chondrocytes apoptosis regulated by FoxO3a dephosphorylation.