Cellular & Molecular Biology Letters最新文献

Background: Glucocorticoids (GCs) are key regulators of hematopoiesis, but the effects of chronically elevated endogenous GC levels on hematopoietic stem cell (HSC) function and immune cell development remain poorly understood.

Methods: We used a mouse model with adrenocortical cell-specific deletion of hypoxia-inducible factor-1 alpha (HIF1α; P2H1^Ad.Cortex), which results in sustained and systemic elevation of GC. Hematopoietic stem and progenitor cell (HSPC) populations were analyzed phenotypically and functionally. Transplantation assays assessed the regenerative capacity of HSCs. To determine the role of glucocorticoid receptor (GR) signaling, bone marrow from GR-deficient or wild-type donors was transplanted into P2H1^Ad.Cortex or wild-type (WT) recipients.

Results: Chronic GC exposure in P2H1^Ad.Cortex mice resulted in HSPC expansion and promoted HSC quiescence and metabolic restraint. Functionally, these HSCs showed enhanced regenerative capacity with superior donor chimerism upon transplantation. There was a marked increase in myeloid progenitors and their progeny, including monocytes and granulocytes. In contrast, B-cell development was significantly impaired, with a developmental block at the pre-pro-B-cell stage. Transplantation studies confirmed that these effects were dependent on GR signaling.

Conclusions: Our study reveals a critical role for chronic GC-GR signaling in modulating HSC function, promoting myeloid output, and impairing B-cell development. The P2H1^Ad.Cortex mouse model provides a valuable system to study the hematopoietic consequences of prolonged endogenous glucocorticoid exposure and may aid in understanding the hematologic complications of chronic GC therapy.

Cell death is essential for the preservation of tissue homeostasis, regulating inflammatory responses, and shaping immune status. The mechanism of cell death includes apoptosis, pyroptosis, necroptosis, ferroptosis and autophagy. The onset, progression, and unfavorable prognosis of sepsis are closely associated with these pathways. Here, the mechanisms associated with these five major cell death pathways in sepsis are reviewed, emphasizing two core aspects of the condition: excessive inflammation and immune suppression. These pathways play a fundamental role in modulating these characteristics and offer novel therapeutic prospects. The study provides valuable insights and detailed analyses, making a significant contribution to ongoing research in this domain. The interconnected nature of cell death is highlighted, not only by examining the distinct roles of individual pathways but also by exploring the interactions between different pathways and the crosstalk among key signaling molecules or pathways, including the caspase family, gasdermin family, and NF-κB pathway. Further research should continue to investigate well-established cell death mechanisms while also identifying previously unknown pathways. Therapeutic strategies targeting cell death pathways hold broad application potential. However, during the transition from preclinical research to clinical application, several challenges remain, including limitations of experimental models, as well as the safety and efficacy of treatments. Additionally, the development of personalized treatment approaches tailored to the unique immune profiles of patients is crucial for advancing precision medicine. In conclusion, the present review offers an extensive analysis of the diverse roles of cell death in sepsis, with novel insights into disease mechanisms and guiding therapeutic developments.

Palmitoylation is a reversible post-translational lipid modification of proteins, catalyzed by the Zinc finger DHHC domain-containing (ZDHHC) family of palmitoyltransferases. Palmitoylation plays a pivotal role in regulating localization, stability, trafficking, and interactions, thereby contributing to a wide range of cellular processes. Dysregulation of palmitoylation has been implicated in numerous pathological conditions, including metabolic disorders, muscular diseases, mitochondrial disorders, cancer, and neurodegeneration. In this review, we summarize recent advances in understanding S-palmitoylation, emphasizing its critical roles in protein regulation, cellular and physiological processes, and its implications in both health and disease. Additionally, we highlight emerging therapeutic opportunities and novel strategies in therapeutic applications targeting this lipid modification.

Primary bone tumors and bone metastases represent significant challenges in oncology. Radiotherapy is an important adjuvant treatment for several primary bone and musculoskeletal tumors, as well as for palliative care for metastatic bone lesions. While effective in these applications, patients receiving skeletal radiation face a lifelong risk of fragility fracture at the irradiated sites, among other complications. Damage to bone could be reduced by development of tumor-selective radiosensitizers that would enhance the efficacy of radiotherapy, resulting in reducing the radiation dose delivered to the normal tissues. The creation of bone-selective radioprotection and radio-mitigant strategies that could respectively reduce the magnitude of off-target damage and stimulate functional recovery of the healthy bone microenvironment are warranted. Key barriers to progress in this field include the paucity and inconsistency of data on the skeletal effects of radiotherapy, low throughput and high cost of animal models, reproducibility challenges with in vitro experiments, and poor translational relevance of these models, which may not accurately replicate the human bone-tumor microenvironment. Microphysiological systems (MPS) will accelerate progress in this field by enabling rapid and cost-effective investigation while recapitulating the complexity of the bone-tumor microenvironment to more accurately model the collective response to therapy. Here, we summarize the current knowledge on the transient and long-lasting impacts of radiotherapy and explore opportunities for MPS to streamline and expand our knowledge base. We critically evaluate contemporary model systems, including MPS, and offer suggestions for how these systems can be used to efficiently model the intersection of skeletal radiobiology and bone cancer, and accelerate development of combination therapies.

Background: Extracellular vesicles (EVs) derived from M2 macrophages (M2-EVs) play a protective role in the pathogenesis of acute lung injury. However, their roles and mechanisms in abdominal aortic aneurysm (AAA) are unknown.

Methods: The effects of M2-EVs in AAA were examined in ApoE^-/- mice with angiotensin II infusion. After M2 macrophages were stimulated with antisense oligonucleotides of miR221-5p (miR221-5p-ASOs), EVs were extracted and administered to mice via the tail vein. In vitro, the primary bone marrow-derived monocytes (BMDMs) were isolated and co-cultured with human aortic endothelial cells (HAECs) in Transwell chambers.

Results: M2-EVs significantly reduced AAA incidence and maximal aortic diameters, improved fiber continuity, increased α-SMA, and reduced macrophage infiltration in AAA mice. RNA sequencing revealed that miR221-5p was upregulated in M2-EVs and downregulated in AAA. miR221-5p-ASOs reduced the protection of M2-EVs in AAA mice. M2-EVs induced M2 macrophage polarization, while miR221-5p-ASOs had no effect. Moreover, M2-EVs alleviated oxidative stress and inflammatory responses in HAECs. Mechanistically, miR221-5p bound to poly(ADP-ribose) polymerase 1 (PARP-1) mRNA and reduced PARP-1 expression; PARP-1 was bound to protein phosphatase 1ɑ (PP-1ɑ) and negatively regulated its expression. In vitro experiments showed miR221-5p modulated macrophage polarization through the PARP-1/PP-1ɑ/JNK/c-Jun pathway. Macrophage deletion of PARP-1 inhibited AAA formation and phosphorylation of JNK/c-Jun in mice.

Conclusions: miR221-5p in M2-EVs plays a critical role in AAA pathophysiology by modulating macrophage polarization through PARP-1/PP-1ɑ/JNK/c-Jun signaling. M2-EVs and miR221-5p represent promising therapeutic options for AAA.

Background: Despite the comprehensive advancement in the field of cancer therapeutics, there remains an urgent need to identify new pathophysiological mechanisms that can be targeted in isolation or in combination with existing therapeutic regimens. The epithelial-to-mesenchymal transitions (EMT) induced by hypoxia, cytokines, and growth factors involves acquisition of invasive and migratory properties by cancer cells. Epigenetic alterations of DNA methylations and/or histone modifications cause substantial transcriptomic reprogramming in cancer cells during EMT and metastasis, which can be therapeutically targeted by a thorough understanding of the mutual interactions among the epigenetic processes. Previously, the mammalian DNA methyltransferases (DNMTs) have been shown to possess redox- and Ca⁺⁺- dependent active DNA 5mC demethylation activities in addition to the cytosine methylation activity.

Methods: In this study, we have carried out experiments using a range of molecular, cellular, and genome editing approaches including cell culturing, CRISPR/Cas9-editing, si- or sh-RNA-mediated knockdown, quantitative RT-PCR, western blotting, ChIP-qPCR, Na-bisulfite sequencing, EMT and lung colonization assays in conjunction with DNA methylome and DNMT3A ChIP-Seq analyses, RESULTS: We found that active DNA demethylation activity of DNMT3A is essential for hypoxia-induced EMT of the SW480 colon cancer cells, its global genomic DNA demethylation, and promoter DNA demethylation/transcriptional activation of EMT-associated genes including TWIST1 and SNAIL1. DNMT3A also regulates hypoxia-induced HIF-1α binding to and transcriptional activation of the TWIST1 promoter as well as genome-wide DNA demethylation and EMT of breast cancer and liver cancer cells. Mechanistic analysis supports a regulatory model where hypoxia-induced H3K36me3 mark recruits DNMT3A to demethylate CpG in the hypoxia-responsive element (HRE), thereby facilitating HIF-1α binding and activation of the promoters of EMT genes.

Conclusions: Altogether, this study has provided the first demonstration of a physiological function of the active DNA demethylation activity of the DNMTs. Equally important, our findings have revealed a missing link between the HIF-1α pathway and the O₂-sensing KDM pathway both of which are known to be essential for a wide set of normal and disease-associated cellular processes. Finally, the active DNA demethylation activity of DNMT3A has now emerged as a new potential target for therapeutic development to prevent EMT and metastasis of cancer cells.

Clinical trial number: Not applicable.

Background: Ischemic heart disease remains a leading cause of morbidity and mortality worldwide, with myocardial ischemia-reperfusion (I/R) injury significantly contributing to cardiomyocyte death and poor outcomes post-acute myocardial infarction (AMI). Emerging evidence highlights metabolic changes during myocardial injury, particularly in purine metabolism. This study investigates the protective role of xanthosine (XTS), a purine metabolism intermediate, in alleviating I/R injury.

Methods: Neonatal and adult mouse myocardial tissues post-myocardial infarction (MI) were analyzed using untargeted and targeted metabolomics to explore metabolic profiles. The effects of XTS on I/R injury were evaluated in vivo using a murine I/R model and in vitro with hypoxia/reoxygenation-treated neonatal rat cardiomyocytes (NRCMs). Cardiac function, fibrosis, apoptosis, oxidative stress markers, and ferroptosis-related pathways were assessed via echocardiography, biochemical assays, western blotting, and electron microscopy. Integrated drug affinity responsive target stability (DARTS)-based drug target screening and RNA-seq transcriptomic profiling elucidate XTS-mediated mechanisms against I/R injury.

Results: Metabolomics revealed distinct differences in purine metabolism between neonatal and adult mice post-MI, with significant XTS accumulation observed in neonatal hearts. In vivo, XTS treatment in adult mice enhanced left ventricular function, reduced fibrosis, and alleviated lipid peroxidation and mitochondrial damage post-I/R injury. In vitro, XTS significantly improved cardiomyocyte viability, reduced oxidative stress, and mitigated ferroptosis by restoring glutathione peroxidase 4 (GPX4) levels and reducing acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) expression. Mechanistically, XTS stabilized metabolic enzymes, upregulated L-arginine and glutathione (GSH) to mitigate reactive oxygen species(ROS), and inhibited ferroptosis.

Conclusions: XTS, a key purine metabolism intermediate, improves cardiac remodeling and function following I/R injury by suppressing ferroptosis and reducing mitochondrial ROS production. These findings provide novel insights into the therapeutic potential of XTS as an adjunctive treatment for patients with AMI undergoing revascularization.

As the global population trends toward aging, the number of individuals suffering from age-related debilitating diseases is increasing. With advancing age, skeletal muscle undergoes progressive oxidative stress infiltration, coupled with detrimental factors such as impaired protein synthesis and mitochondrial DNA (mtDNA) mutations, culminating in mitochondrial dysfunction. Muscle stem cells (MuSCs), essential for skeletal muscle regeneration, also experience functional decline during this process, leading to irreversible damage to muscle integrity in older adults. A critical contributing factor is the loss of mitochondrial metabolism and function in MuSCs within skeletal muscle. The mitochondrial quality control system plays a pivotal role as a modulator, counteracting aging-associated abnormalities in energy metabolism and redox imbalance. Mitochondria meet functional demands through processes such as fission, fusion, and mitophagy. The significance of mitochondrial morphology and dynamics in the mechanisms of muscle regeneration has been consistently emphasized. In this review, we provide a comprehensive summary of recent advances in understanding the mechanisms of aging-related mitochondrial dysfunction and its role in hindering skeletal muscle regeneration. Additionally, we present novel insights into therapeutic approaches for treating aging-related myopathies.

Background: Disulfidptosis represents a novel type of regulated cell death induced by excessively high intracellular levels of cystine. Targeting disulfide imbalance is considered a promising treatment approach for colorectal cancer (CRC). However, the involvement of disulfidptosis in CRC immunotherapy is undefined.

Methods: Unsupervised clustering was applied to The Cancer Genome Atlas (TCGA) datasets to classify disulfidptosis-related phenotypes. The tumor microenvironment (TME) was characterized using diverse bioinformatics algorithms, including gene set variation analysis (GSVA) for pathway enrichment analysis and CIBERSORT for immune cell profiling. A disulfidptosis-related gene (DRG) signature was generated for stratifying CRC cases, and univariate Cox regression was utilized for identifying prognostic DRGs. Filamin A (FLNA) was pinpointed as a pivotal regulator of disulfidptosis, and its functional impacts on tumor progression and immunotherapy response were further investigated.

Results: Two different groups were determined on the basis of the built disulfidptosis-related signature (DRS), showing distinct clinical outcomes, as well as different pathway activation, drug sensitivity, and immune infiltration patterns. The high-DRS subgroup correlated with poorer prognosis, elevated immunosuppressive cell activity, and reduced cytotoxic immune cell infiltration. FLNA emerged as a critical mediator of disulfidptosis in CRC, with its knockdown suppressing tumor cell migration and invasion in vitro. The FLNA inhibitor PTI-125 attenuated tumor growth and epithelial-mesenchymal transition (EMT), while FLNA depletion reversed glucose-driven metastasis. Notably, combined glucose transporter 1 (GLUT1) inhibition and anti-programmed cell death protein 1 (PD-1) therapy enhanced CD8⁺ T cell recruitment and suppressed EMT.

Conclusions: This study elucidates the interplay between disulfidptosis and the CRC immune landscape, highlighting FLNA as a therapeutic target. These findings suggest that modulating disulfidptosis in conjunction with immunotherapy may offer a novel treatment paradigm for CRC.

Sepsis, a life-threatening condition characterized by organ dysfunction due to dysregulated host response to infection, remains a global health challenge with high morbidity, mortality, and long-term sequelae. The development of sepsis-associated organ dysfunction (SAODs) substantially worsens prognosis. Despite extensive studies, the pathophysiological mechanisms underlying sepsis and SAODs remain unclear. Protein acetylation is a widespread and reversible post-translational modification regulated by acetyltransferases and deacetylases that occurs on both histone and non-histone proteins. This modification plays a critical role in modulating various cellular processes by modifying target proteins. Emerging evidence indicates that acetylation is involved in sepsis and SAODs through regulation of key biological processes. In this review, we discuss the regulatory enzymes and mechanisms of acetylation, highlight their roles in sepsis and associated organ dysfunction, and explore the potential of acetylation modulators as therapeutic agents, offering new insights into understanding sepsis and developing novel therapeutic strategies.