Journal of cellular biochemistry最新文献

Polo-like kinase 3 (PLK3) plays major roles in cell cycle regulation, DNA repair, and cellular responses to hypoxia. Our prior studies demonstrated that PLK3 negatively regulates the hypoxic response by directly phosphorylating and destabilizing HIF-1α and by destabilizing the E3 ubiquitin ligase SIAH2. We also find that PLK3 stabilizes PTEN by direct phosphorylation. Plk3 knockout mice exhibit increased spontaneous tumorigenesis in multiple organs, particularly the lung, at an advanced age. Tumors from these mice tend to be highly vascularized, consistent with the function of PLK3 in the hypoxic response. However, another study only observed increased tumorigenesis in female Plk3 knockout mice. The present study further explored the role of PLK3 in lung tumorigenesis. We find that PLK3 can phosphorylate SIAH2 in vitro, confirming our hypothesis that PLK3 regulates SIAH2 by direct phosphorylation. We detected a negative correlation between the levels of PLK3 and SIAH2 and a positive correlation between HIF-1α and SIAH2 in both human lung adenocarcinoma and squamous cell carcinoma. We observed an increase in lung tumorigenesis in Plk3 knockout mice in the A/J strain background. Our RNA-Seq analysis revealed significantly increased expression of genes involved in oncogenic pathways and the immune response in lung tumors from Plk3 knockout mice. Finally, we find that induced systemic SIAH2 expression promotes CD8 T cell infiltration into subcutaneous tumors in a syngeneic mouse model. Our work further supports the tumor suppressive role of PLK3 in lung cancer and discovered a novel involvement of PLK3 in the regulation of the immune microenvironment of lung tumors.

Lyn kinase, a member of the Src family of kinases, is a critical regulator of immune cell signaling, regulating key processes including activation, proliferation, survival, and apoptosis. Dysregulated Lyn kinase activity causes haematological malignancies, autoimmune disorders, solid tumors, neurodegenerative, cardiovascular, and metabolic disorders. Here, we aimed to provide a comprehensive account of Lyn kinase biology, highlighting its structural features, regulatory roles in immune and cellular signaling, and pathological implications across diseases, including cancers, neurodegenerative disorders, autoimmune diseases, and metabolic disorders. We further examined emerging therapeutic strategies, including small-molecule inhibitors, monoclonal antibodies, and natural compounds, and highlighted the therapeutic potential of Lyn kinase as a promising drug target. Overexpression of Lyn contributes to tumor growth, metastasis, and resistance to treatment in leukaemia, prostate, breast, lung, and pancreatic cancers. Beyond oncology, emerging evidence links Lyn kinase to neuroinflammation, synaptic dysfunction, and metabolic regulation, further underscoring its broad disease relevance. Lyn kinase is considered a viable therapeutic target, with ongoing research focusing on small-molecule inhibitors, monoclonal antibodies, and natural compounds like flavonoids and polyphenols that have exhibited promising preclinical and clinical outcomes. We summarized current insights into Lyn kinase biology, highlighting its pathological significance and discussing therapeutic opportunities arising from the modulation of this enzyme.

Myocardial ischemia/reperfusion injury (MIRI) commonly arises during medical procedures for coronary artery disease (CAD), a global health issue. Inhibiting autophagy-dependent ferroptosis has emerged as an effective strategy for MIRI treatment, yet its precise mechanisms warrant further exploration. A murine model of myocardial ischemia/reperfusion (I/R) was employed, and cardiac myocytes were subjected to hypoxia/reoxygenation (H/R). Myocardial tissue alterations were assessed using Evans blue/TTC staining, HE staining, and TUNEL assays. An automated biochemical analyzer was used to quantify serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels. Myocardial cell viability was evaluated using Cell Counting Kit-8 (CCK-8) assays. The interaction of the ATG7 promoter with SPI1 was explored through ChIP experiments. The expression levels of autophagy markers (Beclin-1, LC3The expr, ATG7, and SPI1 were assessed via immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot analysis. Various indicators, including LDH, ROS, MDA, Fe2 + , GSH, GPx4, and FTH1, were measured to characterize the ferroptosis process. In MIRI model mice, autophagy-dependent ferroptosis clearly occurred, and ATG7 expression was elevated. ATG7 knockdown effectively alleviated MIRI and inhibited autophagy-induced ferroptosis. SPI1 was identified as a key regulator in this process. SPI1 bound to the ATG7 promoter region, enhancing ATG7 transcription during myocardial I/R and thereby modulating both ferroptosis and autophagy. SPI1 knockdown inhibited ferroptosis and alleviated MIRI by suppressing autophagy. The results of our study revealed that SPI1 promoted ATG7 transcription, exacerbating ferroptosis in MIRI. These findings suggest that therapeutic strategies targeting ferroptosis and autophagy may mitigate cardiovascular diseases in MIRI.

The myelodysplastic syndrome (MDS) is group of clonal hematopoietic stem cell disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular bone marrow, and a high risk of conversion to acute myeloid leukemia. TP53 is a tumor suppressor gene that plays an important role in tumor suppression. Decitabine (DAC) monotherapy has been shown to improve the response rates in TP53-mutated MDS, while the molecular mechanisms of clinical responses are unclear. This study aimed to initially evaluate the TP53 gene locus mutation and the regulation mechanism of DAC on gene expression in AML-MDS cell lines. We detected the mutation of TP53 gene locus in three myeloid tumor cell lines, SKM-1 (mutTP53), M-07e (wtTP53) and HL60 (nullTP53). Then, we performed transcriptomic and proteomic and methylation data in M-07e (wtTP53) and SKM-1 (mutTP53) cells and screened out LGALS1, which is a poor prognostic indicator, as the potential target of TP53 by comparing analysis. We uncovered 31 potential key genes showing differential early responses to DAC treatment in TP53-mutant versus wild-type cells, which may be associated with resistance development. This study revealed the potential molecular mechanisms of TP53 gene locus mutation in DAC-treated MDS.

The accumulation of misfolded proteins within cells, often induced by stress, is a major contributor to cellular dysfunction. Heat shock proteins, which serve as critical chaperone molecules in response to stress-related damage, are essential for maintaining protein homeostasis within cells. In this family of proteins, Heat Shock Protein 72 (Hsp72) stands out for its acute responsiveness to thermal stress. It can swiftly be produced in reaction to the surge of misfolded proteins caused by heat, thus maintaining the equilibrium of intracellular protein metabolism. This analysis explores the function of Hsp72 in maintaining protein homeostasis, focusing on its ability to assist in the refolding of incorrectly folded proteins and to guide their breakdown through the ubiquitin-proteasome and autophagy systems. Furthermore, the potential mechanisms through which cells may eliminate misfolded protein aggregates via the secretory autophagy pathway under heat stress conditions are explored. This study systematically analyzes the various mechanisms by which Hsp72 influences misfolded protein metabolism and discusses the relevance of each pathway in the context of heat stress. Integrating findings from prior laboratory research, it is concluded that Hsp72 plays a pivotal role in regulating misfolded protein metabolism through the secretory autophagy pathway, thereby sustaining intracellular protein homeostasis during heat stress. This investigation expands the functional network of Hsp72 in maintaining protein homeostasis and elucidates the molecular pathways involved in its regulation of misfolded protein metabolism under heat stress, providing a framework for future research on Hsp72's role in cellular recovery from heat stress.

Paracellular permeability of mineral ions and water in the intestines is restricted by claudins (CLDNs), which are key components of tight junctions (TJs). Glutamate (Glu) plays a role in regulating absorption mechanisms in the intestines, but the effect on paracellular permeability remains unclear. In mouse intestine-derived MCE301 cells, Glu treatment increased the mRNA levels of CLDN10b, while the levels of other CLDNs and zonula occludens-1, a scaffolding protein in TJs, remained unchanged. Similar results were obtained in rat intestine-derived IEC6 cells without CLDN1 and CLDN15. Glu also increased the protein level and TJ localization of CLDN10. The Glu-induced increase in CLDN10b mRNA expression was suppressed by knockdown of taste receptor type 1, T1R1 and T1R3. Glu treatment stimulated Ca²⁺ influx, which was inhibited by BAPTA, a Ca²⁺ chelator, and ebselen, a voltage-dependent Ca²⁺ channel inhibitor. Furthermore, the upregulation of CLDN10b mRNA by Glu was inhibited by BAPTA, ebselen, and rapamycin, an inhibitor of mammalian target of rapamycin (mTOR). These results suggest that Glu upregulates CLDN10b expression in MCE301 cells mediated by a T1R1/T1R3-Ca²⁺-mTOR signaling pathway. The mRNA levels of CLDN10b were decreased in the colon of aged mice and MCE301 cells treated with tenovin-1 (Ten-1), an inducer of cellular senescence. Glu reversed the Ten-1-induced reduction of CLDN10b mRNA and restored paracellular barrier function. These results suggest that Glu enhances the intestinal paracellular barrier function through the regulation of CLDN10b expression.

Cancer is a major global health problem. Considering the special role of lactoferrin (Lf) in inhibiting the growth of cancer cells, a new approach has emerged for cancer treatment. The present study aimed to investigate the effect of Lf on the expression level of autophagy-apoptotic genes ATG5, ATG3, and ATG12 in breast cancer cell line MCF7 and an in silico study of the interaction between lactoferrin and the promoter of these genes and their proteins. The survival percentage of MCF7 cells in concentrations of 200, 300, and 500 µg was 94.4%, 91.64%, and 52%, respectively. The expression level of the ATG3 gene in treatment with different concentrations of Lf was increased, but for the ATG5 gene, it decreased. The expression level of the ATG12 gene in cancer cells treated with Lf concentrations of 200 and 300 µg/ml was increased; however, it decreased at the concentration of 500 μg/ml. All concentrations significantly differed from the control (p < 0.05). The interaction of lactoferrin with ATG3, ATG5, and ATG12 proteins showed that the N-lobe region of the lactoferrin interacted with the N-lobe, catalytic domain, and the HR domain of the ATG3 protein, with the HR domain and the UblB domain of the ATG5 protein, and with the C domain of the ATG12 protein. Analysis of HADDOCK data showed that Lf interacted with the promoter of the genes. Lf, in addition to its effect on the expression of the genes, also interacts with the promoter of genes and their protein.

Vitamin A, E, and other vitamins have been demonstrated to potentially be used in the treatment of brain injury in preterm infants; however, whether all types of vitamins can be utilized for this purpose remains unclear. In this study, we systematically investigated the therapeutic mechanisms of vitamins in preterm infant brain injury using network pharmacology and molecular docking techniques. A total of 23 potential targets for four vitamin components against preterm infant brain injury were identified through public databases. Key genes mediating preterm infant brain injury were obtained via transcriptome analysis of human cells from the GEO database. The intersection of therapeutic targets for brain injury and key genes revealed potential targets for vitamin action in the treatment of preterm infant brain injury. Protein-protein interaction (PPI) analysis identified two key targets (PFKFB3 and PDGFRB). KEGG pathway and GO enrichment analyses elucidated the critical pathways. Molecular docking results indicated that the key targets effectively bind with vitamin components (E and Vitamin K) through hydrogen bonds and hydrophobic interactions. This study theoretically explores the potential mechanisms of vitamin therapy for preterm infant brain injury and provides a preliminary theoretical basis for the development and application of vitamins as potential functional therapeutic agents for preventing brain injury in preterm infants.