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.

摘要: Degeneration of the cochlear spiral ganglion neurons (SGNs) is one of the major causes of sensorineural hearing loss and significantly impacts the outcomes of cochlear implantation. Functional regeneration of SGNs holds great promise for treating sensorineural hearing loss. In this study, we systematically screened 33 transcriptional regulators implicated in neuronal and SGN fate. Using gene expression array and principal component analyses, we identified a sequential combination of Ascl1, Pou4f1 and Myt1l (APM) in promoting functional reprogramming of SGNs. The neurons induced by APM expressed mature neuronal and SGN lineage-specific markers, displayed mature SGN-like electrophysiological characteristics and exhibited single-cell transcriptomes resembling the endogenous SGNs. Thus, transcription factors APM may serve as novel candidates for direct reprogramming of SGNs and hearing recovery due to SGN damages.

摘要: Collagenase digestion (d) and cellular outgrowth (og) are the current modalities of meniscus fibrochondrocytes (MFC) isolation for bioengineering and mechanobiology-related studies. However, the impact of these modalities on study outcomes is unknown. Here, we show that og- and d-isolated MFC have distinct proliferative capacities, transcriptomic profiles via RNA sequencing (RNAseq), extracellular matrix (ECM)-forming, and migratory capacities. Our data indicate that microtissue pellet models developed from og-isolated MFC display a contractile phenotype with higher expressions of alpha-smooth muscle actin (ACTA2) and transgelin (TAGLN) and are mechanically stiffer than their counterparts from d-MFC. Moreover, we introduce a novel method of MFC isolation designated digestion-after-outgrowth (dog). The transcriptomic profile of dog-MFC is distinct from d- and og-MFC, including a higher expression of mechanosensing caveolae-associated caveolin-1 (CAV1). Additionally, dog-MFC were superior chondrogenically and generated larger-size microtissue pellet models containing a higher frequency of smaller collagen fibre diameters. Thus, we demonstrate that the modalities of MFC isolation influence the downstream outcomes of bioengineering and mechanobiology-related studies.

摘要: G protein-coupled receptor-associated sorting protein 2 (GPRASP2) has been identified as the causative gene for X-linked recessive syndromic hearing loss (SHL) in our previous study. However, the role of GPRASP2 in auditory function remains unclear. The present study demonstrated that Gprasp2 overexpression in mouse organoids promoted the proliferation of supporting cells (SCs), which was mainly mediated by the Hedgehog signalling pathway. Meanwhile, GPRASP2 promoted hair cell (HC) formation from SCs via beta-catenin signalling. In addition, GPRASP2 deficiency resulted in increased lysosomal degradation of SMO protein, leading to decreased expression of beta-catenin and the Hedgehog pathway transcription factor GLI1. In neomycin-treated mouse cochlear explant, the smoothened agonist (SAG) recured the HC loss and further facilitated AAV-ie-Gprasp2 to promote the proliferation of SCs and formation of HCs. Our results suggested that GPRASP2 could be a potential candidate for gene therapy in the regeneration of HCs.

摘要: Inflammation serves as the foundation for numerous physiological and pathological processes, driving the onset and progression of various diseases. Histone deacetylase 3 (HDAC3), an essential chromatin-modifying protein within the histone deacetylase superfamily, exerts its transcriptional inhibitory role through enzymatic histone modification to uphold normal physiological function, growth, and development of the body. With both enzymatic and non-enzymatic activities, HDAC3 plays a pivotal role in regulating diverse transcription factors associated with inflammatory responses and related diseases. This review examines the involvement of HDAC3 in inflammatory responses while exploring its therapeutic potential as a target for treating inflammatory diseases, thereby offering valuable insights for clinical applications.