Molecular and Cellular Biochemistry最新文献

AlkB homolog 5 (ALKBH5) has been implicated in tumor progression, however, its specific role in angiogenesis in gastric cancer (GC) and the underlying mechanisms remain poorly understood. Messenger RNA (mRNA) expression levels of vascular endothelial growth factor A (VEGFA), ALKBH5, and long non-coding RNA PVT1 (lncRNA PVT1) in GC and paracancerous tissues were measured by quantitative real-time polymerase chain reaction (qRT-PCR). RNA sequencing (RNA-seq) was employed to identify downstream effectors of lncRNA PVT1. The effects of ALKBH5 and lncRNA PVT1 on angiogenesis were examined in vitro and in vivo. The impact of ALKBH5 on the stability of lncRNA PVT1 and VEGFA RNAs was evaluated by mRNA stability assays, and interactions between ALKBH5 and these RNAs were validated using methylated RNA immunoprecipitation (MeRIP) assay. A significant positive correlation was observed among ALKBH5, lncRNA PVT1, and VEGFA expression in both The Cancer Genome Atlas (TCGA) GC database and sixty GC tissue samples. ALKBH5 and lncRNA PVT1 enhanced angiogenesis in AGS and HS746T cells both in vitro and in vivo. RNA-seq revealed that lncRNA PVT1 upregulated VEGFA mainly through the IL17RA/STAT3 signaling pathway. Additionally, ALKBH5 was found to stabilize both lncRNA PVT1 and VEGFA RNAs. MeRIP assays confirmed the direct binding of ALKBH5 to specific sites on lncRNA PVT1 and VEGFA RNAs. In conclusion, ALKBH5 promotes GC angiogenesis primarily through its m6A demethylase activity on targets such as lncRNA PVT1, which regulates VEGFA expression by modulating IL17RA/STAT3 signaling axis. ALKBH5 may serve as a promising biomarker and therapeutic target in GC.

APOBEC3B (A3B), a key cytosine deaminase, plays a multifaceted role in the malignant progression of various cancers. However, the precise role of A3B in prostate cancer (PCa) remains largely elusive. This study aimed to investigate the functional significance of A3B in PCa and evaluate its potential as a therapeutic target. We first demonstrated that A3B is significant upregulated in PCa tissues and positively correlated with higher Gleason scores, poorer prognostic outcomes, and an increased frequency of cytosine deamination-induced mutagenesis. Functional enrichment analysis further revealed that A3B is closely associated with biological processes such as "cell cycle regulation" and "epithelial-mesenchymal transition (EMT)." To validate the biological role of A3B in PCa cells, we conducted a series of in vitro assays, including CCK-8, EdU, colony formation, and transwell migration/invasion. Notably, A3B knockdown suppressed the proliferation of PC-3 cells and reduced their migratory and invasive capabilities by modulating EMT. Conversely, A3B overexpression enhanced these effects in 22RV1 cells. In vivo tumor xenograft experiments further supported our findings, confirming that A3B promotes the growth of PCa cells in mice. Mechanistically, p53 was identified as a suppressor of A3B expression, thereby alleviating genomic instability. Additionally, a combination of multiplex immunofluorescence (mfIHC) and qRT-PCR analyses validated that elevated A3B expression correlates with increased infiltration of immunosuppressive cells, including regulatory T cells (Tregs), CD8 + PD-1 + T cells, and CD163 + macrophages. This infiltration may be mediated by cytokines and chemokines. Collectively, these findings suggest that A3B holds potential as a novel prognostic biomarker and immunotherapeutic target for PCa.

Circadian rhythms are inherent biological cycles that govern vital physiological processes, aligning with external signals such as light and food consumption. These rhythms, which originated over 2.5 billion years ago as a defense against oxidative stress, are essential for maintaining genomic stability by regulating DNA repair pathways, oxidative stress responses, and cell cycle regulation. Alterations in circadian rhythms are increasingly attributed to modern lifestyle practices, including irregular sleep schedules, prolonged exposure to artificial light, and shift work. These disturbances are closely linked to increased oxidative damage and genomic instability, both of which are essential for the development of cancer. There is growing evidence linking circadian misalignment to cancer, and the International Agency for Research on Cancer (IARC) has categorized shift employment that disturbs circadian rhythms as a potential carcinogen. Sleep deprivation intensifies this imbalance, resulting in heightened DNA damage and compromised repair processes. This disturbance is especially alarming in younger individuals, as chronic circadian misalignment may contribute to increasing prevalence of early-onset cancers, including hormone-related malignancies. This review examines the impact of oxidative stress-induced instability and the function of circadian rhythms in mitigating these effects. It underscores the critical influence of sleep deprivation on circadian misalignment and its associated cancer risk implications. Comprehending these relationships is essential for formulating preventive strategies and enhancing cancer treatments, thereby aligning therapeutic interventions with the body's intrinsic biological clock. Mitigating lifestyle-induced circadian disturbances may be crucial in alleviating the increasing incidence of early-onset malignancies in younger adults.

Chronic kidney disease (CKD) is a comprehensive disease characterized by renal injury and decreased renal function, which can lead to increased cardiovascular and all cause mortality rates, seriously affecting the quality of life and lifespan of patients. At present, although renal function decline can be treated with hormone drugs and immunosuppressive drugs, these treatment methods have not shown any beneficial effects on preventing CKD from progressing to renal failure. Dietary intervention has always been one of the cornerstones of CKD treatment, and nephrologists use dietary intervention to reduce symptoms and metabolic complications of CKD and potentially prevent its progression. This review discusses the relationship between kidney disease and amino acids. In addition, we emphasize the regulatory role of amino acid signaling pathways in the progression of CKD, with a focus on causal relationships and potential mechanisms.

M1 macrophage exosomes (M1-Exos) have been shown to play a significant role in regulating Lung adenocarcinoma (LUAD) progression. Krüppel-Like Factor 6 (KLF6) is a widely expressed nuclear transcriptional regulator involving in various key cellular processes and functions as a tumor suppressor. Here, this study aimed to investigate the role of KLF6 in LUAD and whether M1-Exos function in LUAD by KLF6. Levels of mRNA and protein were detected using qRT-PCR and western blotting. Exosomes were isolated from M1 macrophages and co-cultured with LUAD cell lines for functional analysis. In vitro analyses were conducted using 5-ethynyl-2'-deoxyuridine assay, flow cytometry and transwell assay. The N6-methyladenosine (m6A) modification profile was analyzed using the methylated RNA immunoprecipitation assay and the interaction was determined by RNA Immunoprecipitation assay. The murine model was established for in vivo analysis. M1 macrophage exosomes suppressed LUAD cell proliferation, migration and invasion. Further analyses showed that KLF6 was packaged in M1 macrophage exosomes and could be transferred into LUAD cells. Functionally, the incubation of KLF6-decreased M1 macrophage exosomes led to the enhancement of LUAD cell proliferation, migration and invasion. Mechanistically, alkylation repair homolog protein 5 (ALKBH5), an RNA m6A demethylase, could reduce KLF6 m6A modification and then broke the stabilization of KLF6 and decreased its expression in M1 macrophages and LUAD cells. Importantly, ALKBH5 reversed the anticancer effects of M1-Exo on LUAD cells. Moreover, the inhibition of LUAD tumor growth in vivo mediated by M1-Exo was also impeded by ALKBH5. In conclusion, M1 macrophage exosomes inhibited LUAD growth by reducing ALKBH5-mediated KLF6 demethylation.

Mitochondria are highly dynamic organelles essential for cellular energy production. However, they are also a primary source of reactive oxygen species, making them particularly vulnerable to oxidative damage. To preserve mitochondrial integrity, cells employ quality control mechanisms such as mitophagy, a selective form of autophagy that targets damaged or dysfunctional mitochondria for degradation. Among the key regulators of mitophagy are the sirtuins, a family of NAD⁺-dependent deacetylases. SIRT1, SIRT3, and SIRT6 generally promote mitophagy, whereas SIRT2, SIRT4, SIRT5, and SIRT7 often act as negative regulators. Sirtuin-mediated regulation of mitophagy is critical for maintaining cellular homeostasis and is implicated in a variety of physiological and pathological conditions. The aim of this review is to provide an overview focused on describing how sirtuins influence the mitophagy process. It highlights the different molecular mechanisms by which individual members of the sirtuin family modulate mitophagy, either by promoting or suppressing it, depending on the context. In addition, the review explores the relevance of sirtuin-regulated mitophagy in health and disease, emphasizing some conditions under which altered sirtuin activity could be harnessed for therapeutic benefit.

Neutrophil extracellular traps (NETs) are positively correlated with the severity of calcific aortic valve disease (CAVD). This study aims to elucidate the mechanism by which NETs contribute to CAVD. The CAVD mice model was established by calcification-promoting diets, and NETs formation was modulated via intraperitoneal injection of Cl-amidine. We observed the effect of NETs on Raw264.7 cells by regulating NETs and TLR9 in vitro. Concentrations of TNF-α, MPO-DNA complex, and IL-10 were measured using ELISA. NETs formation was assessed through immunofluorescence assay citrullinated histone H3 (citH3). Expression levels of BMP2, RUNX2, IL-1β, TNF-α, IL-10, and TLR 9 were analyzed by qRT-PCR and Western blotting, while flow cytometry was used to assess the expression of CD86 and CD206 on Raw264.7 cells. Results indicated that compared to the vehicle group, the CAVD group exhibited significant valve thickening and increased calcium deposition, as well as elevated levels of inflammatory factors TNF-α and IL-1β, NET-related markers MPO-DNA complexes and citH3, ossification factors BMP2 and RUNX2, and TLR9. Conversely, IL-10 levels were significantly reduced. Cl-amidine intervention in early CAVD mice significantly improved valve thickness and reduced calcium deposition, inflammatory factors, NETs-related markers, ossification factors, and TLR9 levels, while increasing IL-10 levels. Cl-amidine may delay CAVD progression in mice by reducing NETs. In vitro studies confirmed that serum from CAVD mice induced NETs, promoting the polarization of Raw264.7 cells to the M1 phenotype via TLR9 signaling pathway, thereby releasing pro-inflammatory factors (TNF-α, IL-1β, and IL-6), and inhibiting M2 polarization and IL-10 expression. In summary, our findings suggest that NETs promote Raw264.7 cell polarization to M1 through the TLR9 signaling pathway, contributing to the inflammatory response in CAVD. This study proposes a novel therapeutic strategy targeting NETs to delay CAVD progression.