Molecular and Cellular Biology最新文献

Paeonol (Pae) exhibits potent anti-inflammatory and antitumor effects. Chronic atrophic gastritis (CAG) is considered a gastric precancerous lesion, and the JAK2/STAT3 pathway plays a key role in gastrointestinal inflammation and tumorigenesis. Whether Pae ameliorates CAG by regulating this pathway remains unclear. A 1-methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced malignant transformed cell (MC) model and a CAG rat model were established. The malignant biological behaviors of MC cells were assessed using the Cell Counting Kit-8 (CCK-8) assay, clone formation, and Transwell assays. Gastric histopathological changes were examined by pathological staining, inflammatory factors and gastric mucosa-associated factors were detected via enzyme-linked immunosorbent assay (ELISA). Inflammation, proliferation, epithelial-mesenchymal transition (EMT), and the JAK2/STAT3 pathway-related protein expression was analyzed by Western blotting. MC cells exhibited enhanced proliferation, migration, invasion, and EMT, all of which were significantly suppressed by Pae treatment. CAG rats showed severe gastric mucosal damage, intestinal metaplasia, collagen fiber disorganization, and increased Ki-67 expression. Pae treatment alleviated histopathological injury, reduced inflammatory factor levels, and promoted gastric mucosa-associated factor synthesis. Furthermore, Pae markedly inhibited the JAK2/STAT3 pathway in MC cells and gastric tissues. In conclusion, Pae suppresses malignant transformation and alleviates gastric histopathological injury in CAG by modulating the JAK2/STAT3 pathway.

Maintenance of genome integrity is crucial for the survival of an organism. However, our genome is constantly being challenged by several processes that cause cellular stress, resulting in chromosomal instability and the onset of diseases like cancer. Therefore, cells have evolved many dedicated pathways to preserve genomic integrity. The cell cycle is one of the precisely regulated cellular pathways in which the entire genome is duplicated, and one complete copy of the genome is transferred to each daughter cell. Genome duplication is initiated at the G1 phase, while complete duplication occurs at the S phase. Then, the duplicated genome is equally divided into progeny cells through mitosis. Thus, any deregulation of G1, S, and mitotic phases contributes to genome instability. In this review, we have highlighted the importance of ubiquitin signaling, especially E3 ligases, in maintaining genome integrity during replication and mitosis, as it controls the activation and inactivation of cell cycle regulator proteins.

Acute pancreatitis (AP) is a life-threatening condition driven by premature pancreatic enzyme activation, leading to systemic complications and multi-organ dysfunction. Chaihu Shugan Powder (CSP) has been reported to mitigate pancreatic injury associated with AP, but the detailed regulatory mechanism was unclear. In our study, we investigated the fundamental mechanism of how CSP attenuated AP injury. The AP models were constructed by applying cerulein in AR42J cells and rats. Individual CSP interventions did not affect normal cell function. CSP partially reversed cerulein-induced cell damage, as reflected by increased cell viability, the level of glutathione (GSH), and ferroptosis protein markers but decreased the contents of inflammatory factor, reactive oxygen species (ROS), malondialdehyde (MDA), Fe²⁺ and iron. CSP activated the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, which in turn reduced ferroptosis in cerulein-exposed AR42J cells. Silencing the PGC-1α gene could partially inhibit the activation of the PGC-1α/Nrf2/HO-1 pathway by CSP in cerulein-induced AR42J cells. In AP rats, CSP alleviated AP-related pathomorphological changes and ferroptosis in rats by activating PGC-1α/Nrf2/HO-1 pathway. Altogether, the mechanism by which CSP alleviated AP injury in rats may be correlated with the activation of PGC-1α/Nrf2/HO-1 pathway.

Alternative splicing is a fundamental mechanism that ensures accurate gene expression, supports cellular adaptability, and expands protein diversity beyond the limits of a fixed gene pool. With aging, splicing fidelity weakens, contributing to decline in RNA homeostasis and disrupting essential cellular functions, including mitochondrial oxidative phosphorylation, genome stability, and immune regulation, and in turn accelerating tissue and organ dysfunction. Evidence from senescent cells, aged tissues, and model organisms shows that altered levels of splicing factors and increased RNA polymerase II elongation rates impair co-transcriptional splicing and promote mis-spliced isoforms that reinforce senescence and drive pathology. Dysfunction of RNA-binding proteins further contributes to aberrant splicing, linking splicing defects to age-related diseases such as atherosclerosis, osteoarthritis, sarcopenia, and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Therapeutic strategies to correct splicing defects, such as antisense oligonucleotides, RNA interference, CRISPR-Cas systems, ADAR-mediated editing, and RNA aptamers, can restore a homeostatic balance of mRNA isoforms. However, major challenges remain, including distinguishing adaptive physiological from pathological splicing 'noise' and achieving targeted delivery to tissues. Despite these obstacles, RNA splicing dysregulation represents a promising avenue to extend health span by reestablishing homeostatic RNA programs, and reinforces the idea that "transcriptomic instability" is a hallmark of aging.

Cancer develops from the unregulated proliferation of cells, influenced by a confluence of genetic mutations and epigenetic modifications that disrupt normal regulatory networks. In recent years, cellular metabolism has emerged as an important factor in controlling epigenetic states by connecting the availability of intracellular metabolites to changes in chromatin. One such metabolite is lactate, a glycolytic by-product produced in large amounts in tumor cells because of the Warburg effect. Lactate has been found to be a substrate for histone lactylation, a recently discovered epigenetic mark that affects gene expression. Although histone lactylation is gaining importance in cancer biology, its functional role in breast cancer remains inadequately elucidated. In this study, we utilized a lactate-deficient cell line created by the knockout of PKM2 to examine the effects of promoter-level histone H3 lysine 18 lactylation (H3K18la) on the regulation of the DNMT3A gene, which subsequently influences SMAD2 expression and modulates the TGF-β signaling pathway and cellular proliferation in breast cancer. Our findings elucidate a novel metabolic-epigenetic axis that cancer cells utilize to drive tumorigenesis.

Gastrointestinal stromal tumor (GIST), the most common gastrointestinal mesenchymal neoplasm, remains poorly understood at the molecular level, limiting precise diagnosis and targeted therapy. This study aimed to systematically identify key GIST-associated genes through multiomic integration and experimental validation. We analyzed three GIST transcriptomic datasets from GEO, corrected batch effects via surrogate variable analysis (SVA), and identified 61 differentially expressed genes (DEGs) using limma. Weighted gene co-expression network analysis (WGCNA) highlighted progression-related modules, which were refined using random forests and LASSO regression to prioritize C3 and complement factor D (CFD), both of which showed robust diagnostic performance (AUC: 0.928 for C3; 0.955 for CFD). Experimental validation confirmed C3/CFD downregulation in GIST tissues, correlating with advanced stage and poor survival. Functional assays demonstrated their tumor-suppressive roles, inhibiting GIST cell proliferation, colony formation, and migration. CIBERSORT analysis linked C3/CFD to altered immune infiltration, while ssGSEA/GSEA implicated their involvement in lipid metabolism and oxidative phosphorylation. These findings establish C3 and CFD as critical tumor-suppressive biomarkers that modulate the immune response and reprogram metabolism, offering new avenues for GIST diagnosis and therapy.

RNA polymerase I (Pol I) is a specialized eukaryotic enzyme responsible for transcribing ribosomal DNA into precursor rRNA, a process that initiates ribosome biogenesis and supports cellular growth, metabolism, and proliferation. Recent structural and mechanistic studies have revealed unique features of Pol I architecture that enable high transcriptional output and tight regulatory control. Pol I activity is dynamically regulated by signaling pathways, epigenetic mechanisms, and chromatin structure, integrating environmental and metabolic cues to fine-tune ribosome production. Dysregulation of Pol I transcription is associated with a wide spectrum of human diseases: hyperactivation is a hallmark of cancer, whereas loss-of-function mutations cause ribosomopathies, leukodystrophies, and neurodegenerative disorders through nucleolar stress. Targeted therapies, including small-molecule inhibitors and emerging peptide-based approaches, are expanding clinical strategies to modulate Pol I activity. Beyond its canonical role, Pol I contributes to genome stability, immune regulation, and host-pathogen interactions, broadening its therapeutic relevance. This review integrates structural, mechanistic, and disease perspectives on Pol I, highlighting how fundamental discoveries are informing the next generation of targeted interventions across oncology, neurodegeneration, developmental disorders, infection, and aging.

p62/SQSTM1 is a multifunctional adaptor protein playing a central role in the regulation of autophagy and stress response pathways in higher eukaryotes. However, its functional relevance in lower eukaryotes like Dictyostelium remains largely unexplored. In this study, we demonstrate that Dictyostelium p62 is crucial for cAMP-mediated development and autophagy. Loss of p62 alters levels of intracellular glucose, cAMP, ubiquitinated proteins and autophagic flux. These defects result in impaired cell aggregation and abnormal fruiting body formation, accompanied by reduced spore viability. Interestingly, pulsing of p62 null cells with exogenous cAMP could partially rescue the developmental defects, implicating a role of p62 in maintaining the intracellular cAMP levels required for starvation stress-induced development. p62 also influences cell-fate decisions during development as its deletion biases cells toward pre-spore differentiation, whereas overexpression promotes pre-stalk lineage. Mechanistically, p62 also modulates autophagy flux potentially via regulating AMPK levels along with cAMP dynamics. Together, these findings position p62 as an evolutionarily conserved key adaptor protein that provides new insights into the molecular mechanisms underlying multicellular development.

Telomeres are crucial for maintaining chromosomal integrity and are characterized by repetitive DNA sequences, which may be stabilized by the shelterin protein complex or by formation of secondary structures, such as G-quadruplexes (G4 DNA). Frequently, subtelomeric regions are decorated with di- and tri-methylated lysine 27 on histone H3 (H3K27me), repressive marks catalyzed by Polycomb Repressive Complex 2 that are associated with facultative heterochromatin in many eukaryotes. Our previous work with the filamentous fungus Neurospora crassa demonstrated that native telomere repeats induce H3K27me at ectopic loci. Here we report investigations into the mechanism of this and demonstrate that some non-native telomere repeats can also induce H3K27me. Hi-C analyses demonstrated that ectopic telomeric repeats can interact with native telomeres. Chromatin immunoprecipitation (ChIP) experiments with an anti-G4-DNA antibody showed that establishment of H3K27me was not correlated with the presence of G4 DNA. Other ChIP experiments demonstrated that the telomere repeat-binding protein TRF-1, which has been demonstrated to be a member of the shelterin complex in other systems, binds to interstitial telomere repeats that induce H3K27me. Tethering experiments revealed that TRF-1 binding is sufficient to induce H3K27me. Together these results suggest that TRF-1 plays a crucial role in establishment of H3K27me, and thus repression, at telomere sequences.

Copper is an essential but potentially toxic nutrient required for a variety of biological functions. Mammalian cells use a complex network of copper transporters and metallochaperones to maintain copper homeostasis. Previous work investigating the role of copper in various disease states has highlighted the importance of copper transporters and metallochaperones. However, questions remain about how copper distribution changes under dynamic conditions like tissue differentiation. We previously reported that the copper exporter ATP7A is required for skeletal myoblast differentiation and that its expression changes in a differentiation dependent manner. Here, we sought to further understand the ATP7A-mediated copper export pathway by examining ATOX1, the copper chaperone that delivers copper to ATP7A. To investigate the role of ATOX1 in a dynamic cellular context, we characterized its protein-protein interactions during myoblast differentiation using the proximity labeling protein APEX2 to biotinylate proteins near ATOX1. We discovered that the ATOX1 interactome undergoes dramatic changes as myoblasts differentiate. These dynamic interactions correlate with distinct phenotypes of ATOX1 deficiency in proliferating and differentiated cells. Together, our results highlight the dynamic interactome of ATOX1 and its contribution to myoblast differentiation.