Cell and Bioscience最新文献

The aggressive proliferation and metabolic adaptability of glioma contribute to poor clinical prognosis, necessitating novel targets concurrently reprogram glioma cells toward a neuron-like, less proliferative, and metabolically suppressed state. Here, we identified neuronal differentiation factor CEND1 as a candidate and explored its impact on glioma growth and metabolism. We demonstrated that CEND1 was significantly reduced in high-grade gliomas and inversely correlated with patient survival. Elevated CEND1 in glioma cells induced a neuron-like morphology, accompanied with attenuated proliferation and migration. CEND1 overexpression suppressed tumor growth and prolonged the survival of animal models of intracranial orthotopic tumor formation. Metabolomics and biochemical assays revealed that CEND1 inhibited PDH activity and mitochondrial oxidative phosphorylation, ultimately reducing ATP levels. Mechanistically, CEND1 activated AMPK to induce cell proliferation arrest and enhance metformin sensitivity. Altogether, our findings reveal that CEND1 coordinates neuronal differentiation with mitochondrial energetic metabolic suppression to exert anti-proliferative function in glioma, supporting its role as a potential target for glioma therapy.

Background: Osteoporosis (OP) could lead to the alteration of bone marrow microenvironment and non-homeostasis of hematopoiesis, which could increase the incidence of hematologic malignancies. However, whether myeloid-biased hematopoiesis occurred and contributed to the leukemogenesis under the condition of OP remains unclear.

Results: This study successfully induced a mouse model for OP by hindlimb unloading, which shows increased myeloid cells and decreased B cells in the peripheral blood (PB). Furthermore, our study demonstrates that the myeloid-biased subset of HSPCs (hematopoietic stem and progenitor cells) with reduced differentiation and apoptosis, including multipotent progenitor 3 (MPP3) and granulocyte-monocyte progenitors (GMPs), were expanded in the OP mice. The expansion of myeloid-biased HSPCs contributes to the accumulation of HSPCs in the bone marrow and increased myeloid cells in the PB of OP mice. In the expanded pool of HSPCs, OP mice specifically enriched subsets were identified and profiled by single cell RNA-seq, including subHSCs from primitive HSCs, MPP3-1 from MPP3, GMP5 from GMPs, MkP2 from megakaryocyte progenitors and EryP1 from erythrocyte progenitors. Meanwhile, those OP-HU mice enriched subsets shared significantly up- and down-regulated genes enriched in chromatin modification and cell differentiation and apoptosis such as Bromodomain-containing protein 4 (Brd4), encoding an important chromatin remodeling protein, and Proteinase 3 (Prtn3). Moreover, the specific transcription factors corresponding to the expansion of subHSCs, MPP3-1, GMP5 and EryP1 in OP-HU mice were identified as Zfp951, Nfic, Maz and Ezh2. Finally, inhibition of BRD4 in vivo could partially restore the phenotype of OP-HU mice and the expression of genes regulating HSPC expansion, differentiation and apoptosis.

Conclusions: First of all, our study shows that OP could induce the unbalanced hematopoiesis and enhances the myeloid-biased hematopoiesis. Secondly, OP mice enriched subsets of HSPCs were identified and characterized with enhanced chromatin remodeling, reduced differentiation and resistance to apoptosis. Finally, this study demonstrate that Brd4 regulated gene programs endow the myeloid-biased subsets of HSPCs with tumor cell-like characters in OP mice, which may increase the incidence of the leukemic evolution. This study sheds light on the importance for the prevention of myeloid leukemogenesis in human with OP.

Non-coding RNAs are critical regulators of cell-to-cell communication in the cardiovascular system, playing pivotal roles in heart development, function, and disease progression. Among these, extracellular vesicles, RNA-binding proteins, and lipoprotein complexes have emerged as key carriers, facilitating the paracrine-and occasionally endocrine-transfer of non-coding RNAs. While extensive evidence supports the role of microRNAs in mediating communication between cardiomyocytes, fibroblasts, endothelial cells, and immune cells, the involvement of long non-coding RNAs and their carriers in cardiac intercellular signaling remains understudied. This review explores how non-coding RNA carriers protect these molecules from extracellular degradation and ensure targeted delivery to recipient cells, enabling precise modulation of gene expression. Furthermore, we highlight the gaps in understanding the mechanisms of non-coding RNA uptake and their implications, which can be addressed through advanced sequencing technologies, such as single-cell RNA sequencing. These tools provide unparalleled insights into non-coding RNA-mediated communication networks in the heart, shedding light on their roles in maintaining homeostasis and driving disease. Finally, we contrast the well-established microRNA-driven communication mechanisms with the emerging significance of long non-coding RNAs. We also discuss how sequencing advancements transform our understanding of non-coding RNA-based signaling pathways in cardiovascular health and disease.

Objective: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD), and there has been growing attention towards the role of epigenetics in its pathogenesis. This study aims to investigate the underlying mechanism by which SET domain-containing lysine methyltransferase 7 (SETD7) modulates the progression of DN.

Methods: SETD7 knockout mice (Setd7^-/-) and wild-type controls (Setd7^+/+) were intraperitoneally injected with Streptozocin (STZ, 50 mg/kg) to induce DN. The mouse mesangial cell line SV40-MES-13 were stimulated by high glucose in vitro.

Results: SETD7 expression was predominantly upregulated in high glucose-induced glomerular mesangial cells (MCs), and in diabetic mice kidney. Notably, SETD7 promoted the transcription of adenosine A_2B receptor (A2BR), which mediated the activation and phosphorylation of JAK2 (p-JAK2) via direct interaction. Subsequently, p-JAK2 facilitated the recruitment of signal transducer and activator of transcription 3 (STAT3) to binding sites. This led to nuclear translocation of STAT3 and transcriptional regulation of target genes, ultimately promoting fibrosis and inflammation. Importantly, SETD7 deficiency reduced A2BR transcription, thereby inhibiting fibrosis and inflammation in high glucose-induced MCs. Consistently with these findings, SETD7 knockout in STZ-induced mice conferred significant protection against renal injury and reduced glomerular fibrosis.

Conclusions: Our results demonstrate an important role and mechanism of SETD7 in DN by promoting fibrosis and inflammation through the A2BR-mediated JAK2/STAT3 signaling pathway. Targeting SETD7 may represent a promising therapeutic strategy for halting the progression of DN.

Cancer-associated fibroblasts (CAFs) exhibit heterogeneity and play diverse roles in prostate cancer (PCa) progression, yet their specific impact via lactate metabolism remains unexplored. This study identifies a CAFs lactate metabolism-associated transcriptomic signature (CLS) through multi-omics analysis and establishes a Lactate Metabolism-Related Clinical Prognostic Index (LMCAFCPI) using machine learning. Lactate metabolism genes from MsigDB, were used to derive CLS from single-cell RNA sequencing (scRNA-seq). Unsupervised clustering divided samples into two risk subgroups, and GSVA and ssGSEA assessed biological functions and immune features. The LMCAFCPI demonstrated superior prognostic performance. A nomogram incorporating Gleason grade, PSA, T-stage, and LMCAFCPI showed stable biochemical recurrence (BCR) prediction. The study also revealed positive correlations between LMCAFCPI and specific immune cells, and validated signature genes in cellular models. CUT-TAG sequence confirmed PA2G4 knockdown in CAFs suppresses PCa proliferation and metastasis by inhibit H3K18la. Overall, LMCAFCPI offers a novel prognostic tool for PCa management and highlights potential targets for future research, with PA2G4 emerging as a potential therapeutic target due to its inhibition of H3K18la in PCa.

Background: microRNA-4284 is associated with various diseases, but its role in Alzheimer's disease remains unclear. This study explores the therapeutic potential of miR-4284 inhibition by targeting the APBA1 and the JAK/STAT3 pathways in AD models.

Results: miR-4284 expression was analyzed in Aβ-treated SH-SY5Y cells and 5xFAD mice. Luciferase assays identified APBA1 as a direct target of miR-4284. Apoptosis, inflammation, and neuronal survival were assessed using qPCR, western blotting analysis, FACS, and immunohistochemistry. The Morris water maze test evaluated cognitive function, while western blotting analysis examined the JAK/STAT3 pathway. miR-4284 was upregulated in AD models. Its inhibition increased APBA1 expression, reduced Aβ accumulation, suppressed apoptosis and inflammation, and enhanced neuronal survival and cognitive function, correlating with JAK/STAT3 activation.

Conclusions: miR-4284 inhibition confers neuroprotection by modulating APBA1 and JAK/STAT3 signaling, suggesting its potential as a therapeutic target for AD.

Background: While Src family kinases (SFKs) are established mediators of some fibrotic diseases, their specific function in endometrial fibrosis is not well defined. Here, we investigated the function and underlying mechanism of B lymphoid tyrosine kinase (BLK), an SFK member, in driving endometrial fibrosis.

Methods: BLK expression was analyzed in the human endometrium and mice uterus, as well as in human endometrial stromal cells (hEndoSCs). Its functional role was assessed using siBLK in TGF-β1-induced hEndoSCs and in the intrauterine adhesion (IUA) mice model with Blk knockdown (IUA^Blk[LKD]).

Results: BLK was overexpressed and activated in the endometrium of IUA patients, the uterus of IUA mice, and TGF-β1-induced hEndoSCs, and was accompanied by high expression of endoplasmic reticulum stress (ERS) hallmarks GRP78 and CHOP. Inhibition of BLK significantly reduced the expression levels of GRP78, CHOP, Collagen I, and α-SMA in TGF-β1-induced hEndoSCs. Endometrial fibrosis was also significantly attenuated in IUA^Blk[LKD] mice. Phospho-activation of BLK was found to rely on its binding with focal adhesion kinase (FAK) to form a complex, and subsequently aggravated endometrial fibrosis by regulating ERS.

Conclusions: Our findings clarified the critical role and possible mechanism of BLK in endometrial fibrosis. BLK may serve as a promising target for treating endometrial fibrosis.

Background: Males and females exhibit pronounced disparity in the epidemiology, clinical progression, and therapeutic outcomes of colonic diseases, but the underlying mechanisms that regulate sexual dimorphism of colon remain poorly understood.

Results: We determined the colon as a pivotal androgen metabolic hub, where gonad-derived androgens drive sex-dimorphic levels, while androgen-metabolizing enzymes maintain androgen homeostasis in colon. We identified IL-33⁺ colonic stromal cells as the dominant AR-expressing population in colon. Mechanistically, sex-biased androgen levels govern the nuclear translocation of androgen receptor and further assembly of AR liquid-liquid phase-separated condensates in the immunomodulatory stromal cells of male colon. Notably, we uncovered AR-directed transcriptional programs via nuclear AR phase separation underlying sex-biased expression of key factors, including SerpinA3N and MT1, thereby defining molecular base for sex disparities through gonad-colon axis.

Conclusion: These findings provide molecular and cellular base for sex disparities through an androgen-IL33⁺ stromal cell axis in colon.

Background: Triple-negative breast cancer (TNBC) is considered a highly heterogeneous disease. Androgen receptor (AR)-positive TNBC is a subtype with distinct molecular features. However, the molecular mechanism underlying the modulation of the AR signaling pathway in TNBC is still elusive.

Results: BPTF-associated protein of 18 kDa (BAP18) was significantly upregulated in AR-positive TNBC samples and was positively correlated with advanced disease stage and poor prognosis. BAP18 was shown to act as a transcriptional corepressor of AR in AR-positive TNBC cells and is involved in the promotion of AR-positive TNBC. Mechanically, BAP18 associates with AR and the SIN3A/HDAC subcomplex. BAP18 facilitates the recruitment of SIN3A/HDAC to androgen response elements (AREs) in the promoter regions of P21 and PTEN, subsequently leading to a reduced level of histone H4 acetylation on AREs.

Conclusion: Our study revealed that BAP18, which acts as a novel AR corepressor, is involved in AR-positive TNBC progression, suggesting that BAP18 could be a potential therapeutic target for AR-positive TNBC patients.

Background: Immunoglobulin D (IgD) has historically been considered as a surface marker of mature B cell with its specific function being undefined. Until now, no evidence had been presented to suggest that IgD is also expressed in pro-B cells. This study was designed to elucidate the significance for IgD in early B cell development.

Results: Here we developed a mouse model with a targeted deletion of IgD, and assessed the production of the IgM, IgG and IgA, as well as the generation of the antigen specific antibodies. The findings indicated no significant differences in these Ig levels between wild-type and IgD-deficient mice. However, we observed a notable reduction in the number of mature B cells, which led us to the surprising discovery that this decrease in B cell count begins at the pro-B cell stage. More significantly, we identified that IgD, in its intact tetrameric structure, is expressed in the nucleus of pro-B cells. Functionally, IgD appears to promote the proliferation of pro-B cells. Mechanistically, IgD exhibits a transcription factor-like activity, and directly binds to the promoter region of E2f3, a pro-proliferative transcription factor to drive the expression of E2f3, thereby promoting pro-B cells proliferation.

Conclusions: Taken together, this novel insight into the physiological significance of IgD in B cell development has important implications for our understanding of immune system function.