Journal of cellular biochemistry最新文献

Macrophage polarization engenders an immunosuppressive microenvironment, thereby facilitating the survival and epithelial-mesenchymal transition (EMT)-like changes of malignant plasma cells. Ubiquitin (Ub), a short polypeptide predominantly involved in proteasome-mediated protein degradation, has been detected extracellularly in body fluids. In certain diseases, it exerts immune-regulatory functions, including the modulation of macrophage polarization. Nevertheless, its immune-regulatory role in multiple myeloma (MM) remains undetermined. This study investigated the role of extracellular ubiquitin (eUb) in macrophage polarization and MM progression. We demonstrated that serum eUb levels were significantly higher in MM patients than in healthy volunteers. Elevated eUb levels were closely associated with a poor prognosis in MM patients. Exposure to eUb induced M2 macrophage polarization, which in turn promoted MM cell proliferation and EMT via the CXCR4/JAK1/STAT3 pathway. Notably, STAT3 was identified as a transcription factor that directly binds to the CXCR4 promoter, enhancing its expression and establishing a positive-feedback loop. Collectively, eUb promotes MM cell proliferation and EMT-like changes by driving M2 macrophage polarization through activation of the CXCR4/JAK1/STAT3 positive-feedback pathway. These findings underscore the pathological significance of eUb in the MM tumor microenvironment and suggest that targeting this pathway may provide novel therapeutic strategies for MM.

Sirtuin 1 (SIRT1) is a NAD⁺-dependent deacetylase belonging to the sirtuin family, which regulates a broad spectrum of cellular processes through deacetylation of both histones in the nucleus and non-histone proteins in the cytosol. Accumulating evidence indicates that biological aging is associated with a marked decline in the expression and activation of SIRT1/SIRT1, which contributes to the onset and progression of various age-related diseases. Conversely, activation of SIRT1 has been shown to mitigate aging-associated cellular anomalies including mitochondrial dysfunction, oxidative stress, and cellular senescence. In this review, we summarize recent advances in understanding the role of SIRT1 in aging and age-associated diseases across various experimental models, and we also discuss current limitations in the field as well as potential future research direction.

Spinal cord injury (SCI) is a severe condition affecting the central nervous system that often leads to varying degrees of motor and sensory impairment. Acute primary SCI is often managed with early surgical intervention; however, secondary SCI generally has a poor prognosis owing to the lack of effective drug therapy, complex pathophysiological processes, and inherent challenges of neural repair. Ferroptosis, a novel form of programmed cell death, is characterised by oxidative damage resulting from iron-mediated accumulation of reactive oxygen species (ROS) and lipid peroxidation (LPO) within cells. This type of cell death is prevalent in various pathological processes. Although research on ferroptosis in SCI is still emerging, some inhibitors (such as target proteins and natural compounds) have shown promising results in preclinical studies. Targeting ferroptosis may be a potential strategy for treating SCI. This paper reviews the current state of research on ferroptosis in SCI by analysing recent literature and proposes future research directions, aiming to provide new insights into SCI treatment.

Specificity protein 7 (Sp7) is essential for osteoblast differentiation and bone formation. In humans, Sp7 gene mutations are associated with skeletal abnormalities, including osteogenesis imperfecta. Ubiquitylation regulates the cellular levels of Sp7 protein. However, the role of the largest class of E3 ubiquitin ligases in the turnover of Sp7 protein remains unknown. Here, we report for the first time that both catalytic subunits of multi-subunit RING-box E3 ligase, Rbx1 and Rbx2, are expressed in the skeletal tissues and during osteoblast differentiation. In situ immunofluorescence and biochemical fractionation revealed that in osteoblasts, Rbx1 and Rbx2 E3 ligase reside in both the cell cytoplasm and nucleus. The coimmunoprecipitation experiment in primary osteoblasts showed that endogenous Rbx1 and Rbx2 E3 ligase form a molecular complex with the Sp7 protein. Both Rbx1 and Rbx2 enzymes target Sp7 protein for ubiquitination. Sp7 protein is degraded by Rbx1 and Rbx2 enzymes in a dose-dependent manner in both osseous and non-osseous cells. Chemical inhibition established the requirement of Rbx1 and Rbx2-mediated ubiquitination and degradation of Sp7 protein by the proteasomal pathway. In-silico analysis identified three evolutionarily conserved lysines, K-55, K-227, and K-229, in the Sp7 protein as potential targets for ubiquitination. A panel of Sp7 deletion and point mutants was generated that established the critical requirement of lysine-55 for Rbx1 and Rbx2-mediated ubiquitination and degradation. Deleting the Rbx2 gene in osteoprogenitors led to a significant accumulation of Sp7 protein, enhanced expression of osteoblast marker genes, and accelerated matrix mineralization.

Microtubules have become an attractive target for human cancer treatment. Several microtubule stabilizers targeting for taxane site have been widely employed for various tumor treatments in clinic. In this study, to discover novel scaffolds of microtubule stabilizers targeting the taxane site, pharmacophore modeling, molecular docking, and naive Bayes classification models were developed and further applied to screen database with 29,158 compounds. Forty agents were filtered out and considered as potential microtubule stabilizers. The MTT assay showed that hit20 exhibited higher antiproliferative activity against H1299 cell, the IC₅₀ value of which was 16.8 μM. The hit20 conspicuously promoted tubulin polymerization in vitro, and disrupted the intracellular microtubule network of H1299 cells. Moreover, the hit20 caused cells to accumulate at G2/M phase, induced cell apoptosis, and significantly inhibited H1299 cell migration. The results of the molecular dynamics simulation revealed that tubulin-hit20 could form a stable complex, inducing the H6-H7 loop and M-loop regions produce greater fluctuation. The ΔG_bind of tubulin-hit20 was—130.77 kJ/mol, and −156.3 kJ/mol for the tubulin-paclitaxel. In summary, the hit20 is a promising microtubule stabilizer targeting the taxane site and should be further investigated for the development of a novel antitumor agent.

Nicotinamide has been reported to promote apoptosis in malignant melanoma cells, however, its mechanism remains unclear. This study aims to predict and analyze the apoptotic targets of nicotinamide in malignant melanoma through network pharmacology and bioinformatics. Experimental validation was conducted to determine whether nicotinamide inhibits PARP1 function and promotes mitochondrial apoptosis in mouse melanoma cells. PARP1 was identified as a key apoptotic target of nicotinamide in malignant melanoma. High PARP1 expression correlated with poor prognosis and was predictive of 1-year survival in melanoma patients. PARP1 was highly expressed in all melanoma subtypes but was not associated with tumor stage or TMB. GSEA revealed three pathways active under low PARP1 expression. Nicotinamide treatment increased apoptosis in B16 melanoma cells, decreased PAR expression, reduced mitochondrial membrane potential, and upregulated mitochondrial apoptotic proteins. GEPIA2 analysis showed that PARP1 is also highly expressed in various other tumors. Nicotinamide promotes apoptosis in mouse melanoma B16 cells, potentially through PARP1 inhibition, thereby mediating the mitochondrial apoptotic pathway in malignant melanoma.

Clinical Trial Number: Not applicable.