Summary Systemic ketogenesis affects murine erythroid differentiation under fasting condition, while less ketone body β OHB boosts fatty acid synthesis and mevalonate pathway along with decreased levels of histone acetylation, which are beneficial for erythroid differentiation and maturation undergoing stressed erythropoiesis. Abstract Erythroid terminal differentiation and maturation depends on enormous energy supply. During periods of fasting, ketone bodies from the liver are transported into circulation and utilized as crucial fuel for peripheral tissues. However, the effects of fasting or ketogenesis on erythroid behavior remain unknown. Here, we generated a mouse model with insufficient ketogenesis by conditionally knocking out the gene encoding the hepatocyte-specific ketogenic enzyme hydroxymethylglutary-CoA synthase 2 ( Hmgcs2 KO). Intriguingly, erythroid maturation was enhanced with boosted fatty acid synthesis in bone marrow of hepatic Hmgcs2 KO mouse under fasting condition, suggesting that systemic ketogenesis has a profound effect on erythropoiesis. Moreover, we observed significantly activated fatty acids synthesis and mevalonate pathway along with reduced histone acetylation in immature erythrocytes under less systemic ketogenesis condition. Our findings revealed an innovative insight to erythroid differentiation, in which metabolic homeostasis and histone acetylation mediated by ketone bodies are essential factors in adaptation towards nutrient deprivation and stressed erythropoiesis.
Delivery systems that provide time and space control have a good application prospect in tissue regeneration applications, as they can effectively improve the process of wound healing and tissue repair. In our experiments, we constructed a novel micro-RNA delivery system by linking framework nucleic acid nanomaterials to micro-RNAs to promote osteogenic differentiation of mesenchymal stem cells.To verify the successful preparation of tFNAs-miR-26a, the size of tFNAs-miR-26a were observed by non-denaturing polyacrylamide gel electrophoresis and dynamic light scattering techniques. The expression of osteogenic differentiation-related genes and proteins was investigated by confocal microscope, PCR and western blot to detect the impact of tFNAs-miR-26a on ADSCs. And finally, Wnt/β-catenin signaling pathway related proteins and genes were detected by confocal microscope, PCR and western blot to study the relevant mechanism.By adding this novel complex, the osteogenic differentiation ability of mesenchymal stem cells was significantly improved, and the expression of alkaline phosphatase (ALP) on the surface of the cell membrane and the formation of calcium nodules in mesenchymal stem cells were significantly increased on days 7 and 14 of induction of osteogenic differentiation, respectively. Gene and protein expression levels of ALP (an early marker associated with osteogenic differentiation), RUNX2 (a metaphase marker), and OPN (a late marker) were significantly increased. We also studied the relevant mechanism of action and found that the novel nucleic acid complex promoted osteogenic differentiation of mesenchymal stem cells by activating the canonical Wnt signaling pathway.This study may provide a new research direction for the application of novel nucleic acid nanomaterials in bone tissue regeneration.
All-inorganic halide perovskite semiconductors have received extensive attention due to their excellent photoelectronic conversion efficiency. Prior studies have reported on compounds CsPbBr
Abstract Cell‐surface engineering holds great promise in boosting endogenous stem cell attraction for tissue regeneration. However, challenges such as cellular internalization of ligand and the dynamic nature of cell membranes often complicate ligand–receptor interactions. The aim of this study is to harness the innovative potential of programmable tetrahedral framework nucleic acid (tFNA) to enable precise, tunable ligand–receptor interactions, thereby improving stem cell recruitment efficiency. This approach involves experimental screening and theoretical analysis using dissipative particle dynamics. The results demonstrate that altering the flexibility and topology of ligands on tFNA changes their cellular internalization and membrane binding efficiency. Furthermore, optimizing the distribution of the mesenchymal stem cell (MSC)‐binding aptamer 19S (Apt19S) on the tFNA enhances the stem cell capture efficiency. Following successful in vitro MSC capture, Apt19S‐modified tFNA is chemically linked to a hyaluronic acid hydrogel, forming an efficient “stem cell catcher” system. Subsequent in vivo experiments demonstrate that this system effectively promotes early stem cell recruitment and accelerates bone regeneration in different bone healing scenarios, including cranial and maxillary defects.
Abstract Objectives Human salivary adenoid cystic carcinoma ( SACC ) is one of the most common malignant tumours of the salivary gland and has strong migratory and invasive ability, which often lead to poor prognosis and lower survival rate. Tumour tissue tends to stiffen during solid tumour progression. This study aimed to investigate the influence of various substrate stiffness on the migration and invasion of SACC . Methods Salivary adenoid cystic carcinoma cell line ACC 2 cells were cultured on polydimethylsiloxane substrates ( PDMS ) with varying stiffness for investigating the effects of substrate stiffness on the activities of MMP s and TIMP s. The underlying mechanism was also explored. Results When ACC 2 cells were cultured on various stiffness of PDMS , the expressions of matrix metalloproteinases 2 ( MMP 2), MMP 9, MMP 14, R hoA, R ac1, Rho‐associated protein kinase 1 ( ROCK 1) and ROCK 2 were up‐regulated with increasing substrate stiffness, whereas that of tissue inhibitor of matrix metalloproteinase 1 ( TIMP 1), TIMP 2 and TIMP 4 were down‐regulated with increasing substrate stiffness. Conclusions Our results showed that substrate stiffness regulated the activities of MMP s and TIMP s and then modulate migratory and invasive ability of ACC 2 cells via RhoA/ ROCK pathway. This work indicate that matrix stiffness played an important role in progression of SACC , which not only can help understand the strong invasive ability of SACC , but also suggested that therapeutically targeting matrix stiffness may help reduce migration and invasion of SACC and improve effective therapies.
Tumor development often requires cellular adaptation to a unique, high metabolic state; however, the molecular mechanisms that drive such metabolic changes in TFE3-rearranged renal cell carcinoma (TFE3-RCC) remain poorly understood. TFE3-RCC, a rare subtype of RCC, is defined by the formation of chimeric proteins involving the transcription factor TFE3. In this study, we analyzed cell lines and genetically engineered mice, demonstrating that the expression of the chimeric protein PRCC-TFE3 induced a hypoxia-related signature by transcriptionally upregulating HIF1α and HIF2α. The upregulation of HIF1α by PRCC-TFE3 led to increased cellular ATP production by enhancing glycolysis, which also supplied substrates for the TCA cycle while maintaining mitochondrial oxidative phosphorylation. We crossed TFE3-RCC mouse models with Hif1α and/or Hif2α knockout mice and found that Hif1α, rather than Hif2α, is essential for tumor development in vivo. RNA-seq and metabolomic analyses of the kidney tissues from these mice revealed that ketone body production is inversely correlated with tumor development, whereas de novo lipid synthesis is upregulated through the HIF1α/SREBP1-dependent mechanism in TFE3-RCC. Our data suggest that the coordinated metabolic shift via the PRCC-TFE3/HIF1α/SREBP1 axis is a key mechanism by which PRCC-TFE3 enhances cancer cell metabolism, promoting tumor development in TFE3-RCC.
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