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摘要: The association between Porphyromonas gingivalis infection and oral squamous cell carcinoma (OSCC) has been established by numerous epidemiological studies. However, the underlying mechanism specific to this connection remains unclear. By bioinformatical analysis, we identified ZFP36 as a potentially significant co-expressed gene in both the OSCC gene database and the persistent infection model of P. gingivalis. To further investigate the role of ZFP36, we established a cell model that human immortalized oral epithelial cells (HIOECs) that were sustainedly infected by P. gingivalis (MOI = 1) for a duration of 30 weeks. Our findings indicated that sustained infection with P. gingivalis inhibited the expression of ZFP36 protein and induced changes in the biological behaviour of HIOECs. The mechanism investigation demonstrated the potential role of ZFP36 in regulating the cancer-related biological behaviour of HIOECs. Subsequent studies revealed that highly expressed CCAT1 could serve as a molecular scaffold in the formation of the ZFP36/CCAT1/MK2 complex. This complex formation enhanced the binding abundance of MK2 and ZFP36, thereby promoting the inhibition of ZFP36 protein phosphorylation. To summarize, low expression of ZFP36 protein under persistent P. gingivalis infection enhances the cancer-related biological behaviour of HIOECs.

摘要: The circadian clock is responsible for the regulation of different cellular processes, and its disturbance has been linked to the development of different diseases, such as cancer. The main molecular mechanism for this issue has been linked to the crosstalk between core clock regulators and intracellular pathways responsible for cell survival. The PI3K/AKT signalling pathway is one of the most known intracellular pathways in the case of cancer initiation and progression. This pathway regulates different aspects of cell survival including proliferation, apoptosis, metabolism, and response to environmental stimuli. Accumulating evidence indicates that there is a link between the PI3K/AKT pathway activity and circadian rhythm in physiologic and cancer-related pathogenesis. Different classes of PI3Ks and AKT isoforms are involved in regulating circadian clock components in a transcriptional and functional manner. Reversely, core clock components induce a rhythmic fashion in PI3K and AKT activity in physiologic and pathogenic conditions. The aim of this review is to re-examine the interplay between this pathway and circadian clock components in normal condition and cancer pathogenesis, which provides a better understanding of how circadian rhythms may be involved in cancer progression.

摘要: Orthodontic tooth movement (OTM) is a highly coordinated biomechanical response to orthodontic forces with active remodelling of alveolar bone but minor root resorption. Such antiresorptive properties of root relate to cementocyte mineralization, the mechanisms of which remain largely unknown. This study used the microarray analysis to explore long non-coding ribonucleic acids involved in stress-induced cementocyte mineralization. Gain- and loss-of-function experiments, including Alkaline phosphatase (ALP) activity and Alizarin Red S staining, quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunofluorescence analyses of mineralization-associated factors, were conducted to verify long non-coding ribonucleic acids taurine-upregulated gene 1 (LncTUG1) regulation in stress-induced cementocyte mineralization, via targeting the Toll-like receptor 4 (TLR4)/SphK1 axis. The luciferase reporter assays, chromatin immunoprecipitation assays, RNA pull-down, RNA immunoprecipitation, and co-localization assays were performed to elucidate the interactions between LncTUG1, PU.1, and TLR4. Our findings indicated that LncTUG1 overexpression attenuated stress-induced cementocyte mineralization, while blocking the TLR4/SphK1 axis reversed the inhibitory effect of LncTUG1 on stress-induced cementocyte mineralization. The in vivo findings also confirmed the involvement of TLR4/SphK1 signalling in cementocyte mineralization during OTM. Mechanistically, LncTUG1 bound with PU.1 subsequently enhanced TLR4 promotor activity and thus transcriptionally elevated the expression of TLR4. In conclusion, our data revealed a critical role of LncTUG1 in regulating stress-induced cementocyte mineralization via PU.1/TLR4/SphK1 signalling, which might provide further insights for developing novel therapeutic strategies that could protect roots from resorption during OTM.

摘要: Drug resistance is perhaps the greatest obstacle in improving outcomes for cancer patients, leading to recurrence, progression and metastasis of various cancers. Exploring the underlying mechanism worth further study. N6-methyladenosine (m6A) is the most common RNA modification found in eukaryotes, playing a vital role in RNA translation, transportation, stability, degradation, splicing and processing. Long noncoding RNA (lncRNA) refers to a group of transcripts that are longer than 200 nucleotides (nt) and typically lack the ability to code for proteins. LncRNA has been identified to play a significant role in regulating multiple aspects of tumour development and progression, including proliferation, metastasis, metabolism, and resistance to treatment. In recent years, a growing body of evidence has emerged, highlighting the crucial role of the interplay between m6A modification and lncRNA in determining the sensitivity of cancer cells to chemotherapeutic agents. In this review, we focus on the recent advancements in the interaction between m6A modification and lncRNA in the modulation of cancer drug resistance. Additionally, we aim to explore the underlying mechanisms involved in this process. The objective of this review is to provide valuable insights and suggest potential future directions for the reversal of chemoresistance in cancer.

摘要: In gene therapy, intravenous injection of viral vectors reigns as the primary administration route. These vectors include adeno-associated viruses, adenoviruses, herpes viruses, rhabdoviruses and others. However, these naturally occurring viruses lack inherent tissue or organ tropism for tailored disease treatment. To address this, we devised an optimized process involving directed viral capsid evolution, organ-specific humanized mouse models and in vitro-in vivo virus screening. Our approach allows for the rapid generation specifically modified adeno-associated virus variants, surpassing the time required for natural evolution, which spans millions of years. Notably, these variants exhibit robust targeting of the liver, favouring chimeric human liver cells over murine hepatocytes. Furthermore, certain variants achieve augmented targeting with reduced off-target organ infection, thereby mitigating dosage requirements and enhancing safety in gene therapy.

摘要: Human organoids recapitulate the cell type diversity and function of their primary organs holding tremendous potentials for basic and translational research. Advances in single-cell RNA sequencing (scRNA-seq) technology and genome-wide association study (GWAS) have accelerated the biological and therapeutic interpretation of trait-relevant cell types or states. Here, we constructed a computational framework to integrate atlas-level organoid scRNA-seq data, GWAS summary statistics, expression quantitative trait loci, and gene-drug interaction data for distinguishing critical cell populations and drug targets relevant to coronavirus disease 2019 (COVID-19) severity. We found that 39 cell types across eight kinds of organoids were significantly associated with COVID-19 outcomes. Notably, subset of lung mesenchymal stem cells increased proximity with fibroblasts predisposed to repair COVID-19-damaged lung tissue. Brain endothelial cell subset exhibited significant associations with severe COVID-19, and this cell subset showed a notable increase in cell-to-cell interactions with other brain cell types, including microglia. We repurposed 33 druggable genes, including IFNAR2, TYK2, and VIPR2, and their interacting drugs for COVID-19 in a cell-type-specific manner. Overall, our results showcase that host genetic determinants have cellular-specific contribution to COVID-19 severity, and identification of cell type-specific drug targets may facilitate to develop effective therapeutics for treating severe COVID-19 and its complications.

摘要: Intervertebral disc (IVD) degeneration is an age-related problem triggering chronic spinal issues, such as low back pain and IVD herniation. Standard surgical treatment for such spinal issues is the removal of the degenerated or herniated IVD and fusion of adjacent vertebrae to stabilise the joint and locally decompress the spinal cord and/or nerve roots to relieve pain. However, a key challenge of current surgical strategies is the increasing risk of adjacent segment degeneration due to the disruption of native biomechanics of the functional spinal unit, dominated by the loss of the IVD. In the past two decades, research has focused on developing a number of bioengineering approaches to repair and regenerate the IVD; in particular, tissue engineering of the IVD, using bioscaffolds and stem cells represents a promising area. This review highlights the current tissue engineering approaches utilising biomaterials, animal models and cell sources for IVD regeneration and discusses future opportunities.

摘要: Senescent cells are characterised by increased glycolysis dependence. Normalisation of glycolysis metabolism is essential for senescence amelioration. However, the mechanism of proteins involved in cellular glycolysis metabolism has not been fully elucidated. Here, we identified a candidate compound, an oxazole analogue (KB2764), that can improve senescence. To elucidate the mechanism of the KB2764, we investigated the interacting proteins. KB2764 interacted with alpha-enolase (ENO1) and pyruvate kinase M (PKM), ultimately allowing PKM to phosphorylate ENO1. KB2764 consequently increased mitochondrial ATP production and reduced reliance on glycolysis. Knockdown of the ENO1 experiment in senescent cells demonstrates that regulation of ENO1 activity is a prerequisite for recovery of mitochondrial function. Furthermore, the action of KB2764 extends its application to extend the lifespan of Caenorhabditis elegans. Taken together, our findings reveal a novel mechanism by which senescence is ameliorated through metabolic reprogramming and mitochondrial functional recovery via KB2764-mediated regulation of ENO1 protein activity.

摘要: Lactate is not only a byproduct of glycolysis, but is also considered an energy source, gluconeogenic precursor, signalling molecule and protein modifier during the process of cellular metabolism. The discovery of lactylation reveals the multifaceted functions of lactate in cellular metabolism and opens new avenues for lactate-related research. Both lactate and lactylation have been implicated in regulating numerous biological processes, including tumour progression, ischemic-hypoxic injury, neurodevelopment and immune-related inflammation. The kidney plays a crucial role in regulating lactate metabolism, influencing lactate levels while also being regulated by lactate. Previous studies have demonstrated the importance of lactate in the pathogenesis of acute kidney injury (AKI) and chronic kidney disease (CKD). This review explores the role of lactate and lactylation in these diseases, comparing the function and metabolic mechanisms of lactate in normal and diseased kidneys from the perspective of lactylation. The key regulatory roles of lactylation in different organs, multiple systems, various pathological states and underlying mechanisms in AKI-to-CKD progression are summarised. Moreover, potential therapeutic targets and future research directions for lactate and lactylation across multiple kidney diseases are identified.