Cellular & Molecular Biology Letters最新文献

Background: Parkinson's disease (PD) lacks disease-modifying therapies. Fibroblast growth factor 21 (FGF21) is implicated in PD, but its neuroprotective mechanisms via fibroblast growth factor receptor 1 (FGFR1)-sirtuin 1 (Sirt1) remain unclear.

Methods: Using 1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine (MPTP)-induced PD mice and lipopolysaccharides (LPS)-stimulated BV2 microglia, this study employed recombinant adeno-associated virus (rAAV)-mediated FGF21 overexpression (OE). Multi-dimensional analyses (behavior, immunofluorescence, molecular docking, Western blot, PCR, transmission electron microscopy (TEM)) assessed FGF21's effects and mechanisms.

Results: FGF21^OE significantly improved motor deficits (gait, rotarod) and non-motor symptoms (depression/anxiety) in PD mice. It repaired the blood-brain barrier (BBB) by upregulating tight junction proteins (claudin, zonula occludens (ZO-1), occludin) and reducing astrocyte activation (glail fibrillary acidicprotein, GFAP). Mechanistically, FGF21 binding to FGFR1 activated Sirt1, enhancing mitochondrial fusion (optic atrophy 1 (OPA1), mitofusin 1 (Mfn1)) and inhibiting fission (dynamin-related protein 1 (Drp1), Fission 1 (Fis1)), improving membrane potential and ultrastructure. FGF21 also activated the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, boosting PINK1/Parkin-mediated mitophagy and inhibiting Casp3/Bax-dependent apoptosis. Furthermore, FGF21 reduced neuroinflammation by suppressing nuclear factor kappa-B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and shifting microglia from pro-inflammatory M1 to anti-inflammatory M2. Molecular docking and co-IP confirmed FGF21 enhances direct FGFR1-Sirt1 interaction, synergistically regulating these pathways.

Conclusion: FGF21 exerts multi-faceted protection in PD via the FGFR1-Sirt1 axis, including BBB repair, mitochondrial homeostasis restoration, microglial polarization towards M2, balancing autophagy and apoptosis, and promoting neuronal survival.

Circular RNAs (circRNAs) play a crucial role in the initiation and development of cancers. Understanding circRNAs' functions and molecular mechanisms in tumor development is expected to reveal new diagnostic indicators and therapeutic targets of prostate cancer (PCa). In our study, we identified a new circRNA hsa-circ-0057553 (circSLC39A10) in PCa from a bioinformatic microarray analysis. The levels of circSLC39A10 were observed to be markedly elevated in both prostate cancer cells and tissues. This increased expression was associated with multiple clinicopathological features, suggesting its potential as a new diagnostic indicator for PCa. CircSLC39A10 exhibited oncogenic effects on the proliferation, migration, invasion, and metastasis of prostate cancer cells both in vivo and in vitro. CircSLC39A10 was identified as a factor that promoted the malignant progression of PCa cells through the miR-936/PROX1/β-catenin pathway, ultimately leading to the activation of Wnt signaling. Overall, circSLC39A10 is an oncogenic circRNA with potential as a biomarker for PCa. The identified circSLC39A10/miR-936/PROX1/β-catenin axis shows promise as an innovative therapeutic target for PCa.

Peroxisome proliferator-activated receptors (PPARs) play a critical role in the development of intervertebral disc degeneration (IVDD), a major contributor to chronic low back pain (LBP). This condition is characterized by excessive nucleus pulposus cell (NPC) death, which contributes to degradation of the extracellular matrix (ECM). Ferroptosis, an iron-dependent cell death mechanism, has emerged as a key player in IVDD. However, the underlying mechanism and pathogenesis remain incompletely understood. In this study, we aimed to assess the function of PPARγ in IVDD and its modulation of ferroptosis in vivo using rat models of IVDD and in vitro using NPC cultures treated with oxidative stress-inducing agents, such as tert-butyl hydroperoxide (TBHP) and interleukin (IL)-1β. NPC treatment with PPARγ agonist (pioglitazone) and inhibitor of ferroptosis (ferrostatin-1; Fer-1) maintained ECM homeostasis by downregulating matrix metalloproteinases and ferroptosis indicators and upregulating anabolic factors. Conversely, PPARγ knockdown exacerbated ferroptosis and ECM degradation, underscoring its protective effects against oxidative stress-induced ferroptosis in NPCs. PPARγ regulates ferroptosis and ECM homeostasis through autophagy. RNA-sequencing, chromatin immunoprecipitation followed by quantitative polymerase chain reaction (ChIP-qPCR) and co-immunoprecipitation (Co-IP) assays confirmed Axl as a novel binding partner of PPARγ. Furthermore, using a Tet-on dual-inducible system, we demonstrated the involvement of the PPARγ-Axl axis in the alleviation of oxidative stress-induced ferroptosis by autophagy. In vivo, PPARγ overexpression in intervertebral disc (IVD) alleviated IVDD in rat models. In summary, these findings reveal a pivotal role for the PPARγ-Axl axis in mitigating ferroptosis and preserving ECM homeostasis in NPC via autophagy, providing a new therapeutic strategy for IVDD.

Aging is a primary risk factor driving the increased prevalence of cardiovascular diseases, significantly contributing to global mortality and healthcare burdens. Aging-related alterations, including genomic instability, telomere shortening, and loss of proteostasis, underpin the pathogenesis of numerous cardiovascular conditions such as heart failure, arrhythmia, cardiomyopathy, myocardial infarction, and atherosclerosis. Recent insights into molecular and cellular mechanisms highlight the roles of senescence, inflammation, mitochondrial dysfunction, and metabolic disturbances in cardiovascular aging. Cellular and vascular senescence further accelerates the development of aging-related cardiovascular diseases. Emerging therapeutic strategies targeting these pathways, such as metabolic regulators, senolytic agents, antioxidants, stem cell-derived exosomes, and natural bioactive compounds, offer promising avenues for mitigating aging-related cardiovascular pathology.

The basic helix-loop-helix (bHLH) transcription factor family plays a crucial role in regulating cellular differentiation and development. Inhibitor of DNA binding 1 (ID1), which lacks a DNA-binding motif, functions as a dominant-negative inhibitor of class I and II bHLH factors to antagonize their abilities to bind to DNA and transcriptionally regulate target genes. Given that hematopoiesis is a dynamic and intricate process involving the differentiation of hematopoietic stem and progenitor cells into mature lineage cell types, elucidating the regulatory role of ID1 as a differentiation inhibitor within the hematopoietic system is paramount. Physiologically, ID1 is indispensable for maintaining normal bone marrow function and cell fate determination. However, aberrant ID1 expression, driven by pathogenic mechanisms, such as gene mutations or oncogenic kinases, contributes to the initiation and progression of various blood disorders, particularly leukemia. In this review, we comprehensively summarize the expression patterns of ID1 in hematopoietic and stromal cells within the bone marrow niche, and delve into its modulation of blood lineage commitment and development. While some discrepancies in the literature may arise from differences in experimental models or detection methods, it is evident that precise ID1 regulation is crucial for myeloid-lymphoid fate decisions. Moreover, ID1 overexpression is a causal factor in hematologic malignancies. Encouragingly, significant strides have yielded promising antileukemic effects of ID1 inhibitors, both alone and in combination with targeted therapies against oncogenic signaling pathways. Nevertheless, further efforts are needed to develop innovative and practical strategies that modulate ID1 activity to restore and sustain hematopoietic homeostasis.

N⁶-methyladenosine (m⁶A) is a novel epigenetic modification that has been reported to be involved in the progression of osteoporosis (OP), providing new insights into the pathogenesis of OP. The methyltransferases KIAA1429 [also known as virus-like m⁶A methyltransferase-associated protein (VIRMA)] participates in various essential biological processes by regulating target gene expression levels. However, the function of KIAA1429-mediated m⁶A modification in OP progression remains unclear. This study aimed to investigate the biological roles and potential underlying mechanisms of KIAA1429 in OP and osteoclast differentiation. scRNA-seq combined with bulk RNA-seq screening for the differential gene KIAA1429. Analysis of clinical data confirmed KIAA1429 expression and its clinical significance in OP. KIAA1429 inhibited osteoclast differentiation in vitro and reduced bone resorption in ovariectomized (OVX) mice. Mechanistically, LRP4 was identified as a downstream target of KIAA1429. KIAA1429 mediated the m⁶A modification of Lrp4 mRNA, and then YT521-B homology-domain-containing protein 1 (YTHDC1) increased Lrp4 stability and expression. In addition, LRP4 enhancement recruited TNFAIP3, which inactivated NF-κB signaling. This novel mechanism of NF-κB signaling pathway inhibition by enhanced KIAA1429/YTHDC1-coupled Lrp4 transcription during osteoclast differentiation highlights the potential of KIAA1429 as a novel predictive biomarker and therapeutic target for OP progression.

Cancer development is a complex process, initiated by the combination of epigenetic and genetic changes in normal cells. Selective microenvironmental pressure within the primary tumors prompts the microevolution of invasive cell lineages that efficiently penetrate circulation and lymphatic systems and extravasate in distant organs, initiating the formation of metastases. Extravasation (diapedesis), i.e., the multistep penetration of the endothelial layer by circulating cancer cells, is regarded as the decisive step and one of the bottlenecks of the metastatic cascade. It limits malignant cancer dissemination, while initiating the formation of metastases. The efficiency of extravasation depends equally on the properties of circulating cancer cells and the local functional status of the endothelium, which remains sensitive to paracrine, adhesive, and juxtacrine stimuli generated by cancer and immune cells. Here, we review the current state of knowledge on the significance of endothelial activation for the diapedesis of circulating cancer cells, with the emphasis on the intercellular communication pathways that mediate this process. We also address the potential and limitations of endothelial activation as the target for novel strategies of cancer treatment.

Background: The Telomeric repeat-binding factor 2 (TRF2) binds to TTAGGG repeats located at chromosomes ends and ensures telomere protection together with the other members of shelterin. In addition to its well-known role in telomere maintenance, TRF2 can also bind to interstitial telomeric sequences and regulate the expression of specific genes with a consequent impact on tumor formation and progression. However, a comprehensive analysis of the impact of TRF2 on global gene expression of human cancer cells and of the underlying mechanisms is still lacking.

Methods: The integration of omics technologies (RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP-seq), interactomics, and microRNA (miRNA) profiling) was used to deeply investigate the extra-telomeric role of TRF2. Differential gene expression and binding sites of TRF2 were confirmed by qRT-PCR while the interaction of TRF2 with TATA-box binding protein associated factor 15 (TAF15) was validated by immunoprecipitation and proximity ligation assay. Finally, target specificity was assessed by luciferase assay and western blotting while biological effects were investigated by cell migration analysis (unpaired t tests was used to calculate statistical significance).

Results: We found that TRF2 impinges on the expression of 717 genes involved in various cancer-related pathways. Unexpectedly, just a small portion of Differentially Regulated genes are directly bound by TRF2, suggesting the existence of alternative mechanisms of TRF2-mediated gene regulation. In particular, we found that TRF2 binds to various noncoding RNA regions and interacts with many RNA binding proteins, supporting TRF2's involvement in noncoding RNA-mediated mechanisms. Through the intersection of omics-analyses, we provided here experimental evidence of a multilayered mechanism of regulation where TRF2, interacting with TAF15, regulates miR-181A1 host gene and mature miR-181a-5p expression, which in turn targets S100A10, a known plasma membrane protein with oncogenic role.

Conclusions: Our work shows, for the first time, a broad overview on the extra-telomeric role of TRF2 in human cancer, further revealing a new axis through which TRF2 contributes to cancer progression.

Background: Phenotypic transformation of Schwann cells (SCs) plays a crucial role in nerve regeneration. Previous studies have demonstrated that Runx2 significantly influences the biological behavior of SCs. Nonetheless, the regulatory mechanisms that govern its epigenetic regulation are not yet fully elucidated.

Methods: To facilitate this investigation, an adenovirus for the overexpression of Runx2 was constructed. Healthy adult Sprague-Dawley rats, weighing between 100 and 150 g and irrespective of sex, were randomly selected for the study. After establishing a model of sciatic nerve crush injury, tissue samples were harvested for histological analysis at both 4 and 7 days post-injury. In vitro, an Runx2-overexpressing SC line was established. Thorough analysis of transcriptome data, coupled with CUT&Tag sequencing of histones and transcription factors in SCs following Runx2 overexpression, was conducted. Additionally, single-cell RNA sequencing data from GSE216665 were incorporated to elucidate the mechanistic role of Runx2. The findings were subsequently validated through dual-luciferase assays.

Results: Following nerve crush injury, Runx2-positive SCs were identified at the injury site. Through comprehensive multiomics analysis, we discovered that lipid metabolism was disrupted in Runx2-overexpressing SCs. Further investigation established a detailed super-silencer landscape in these cells, revealing that elevated Runx2 levels form a super-silencer within the transcriptional regulatory region of the Lpl gene, thereby downregulating Lpl expression.

Conclusions: Runx2 can modulate the biological behavior of SCs by forming super-silencers that interfere with the expression of lipid metabolism genes, such as Lpl, thereby altering the metabolic capacity of SCs.

Background: Capillarization of liver sinusoidal endothelial cells (LSECs) is a central event in response to liver injury. In this study, we investigated the role of Yes-associated protein 1 (YAP1, also known YAP) in LSEC capillarization and liver injury.

Methods: YAP expression was assessed in liver samples from mice injured by CCl₄ injection and DDC diet. EC-specific Yap1 conditional knockout mice (Yap1^∆end) were generated by breeding Yap1^fl/fl mice with Cdh5-Cre^ERT2 mice. HA-PEI/siYap1 nanoparticles were applied to specifically inhibit YAP expression in LSECs.

Results: YAP was primarily expressed in LSECs, and its expression was elevated during liver fibrosis. EC-specific Yap1 deficiency significantly increased the fenestrae in LSECs and mitigated hepatocyte death and liver fibrosis. Overexpression of YAP in EC aggravated capillarization, hepatocyte death, and liver fibrosis. Mechanistically, YAP inhibited Gata6 transcription via binding to its promoter and thus resulted in LSEC capillarization. Overexpression of GATA6 in EC alleviated capillarization and liver fibrosis by activating Nos3 transcription. Moreover, specific delivery of HA-PEI-siYap1 nanoparticles to LSEC alleviated liver injury in mice.

Conclusions: YAP-GATA6/eNOS signaling is essential in LSEC capillarization and subsequent hepatocyte death. Interventions targeting YAP in LSECs offer a promising strategy for the treatment of liver fibrosis.