Molecular and Cellular Biochemistry最新文献

Glomerulonephritis (GN) is a general term which encompasses various types of glomerular disorders characterized by damage to the capillary endothelium, basement membrane, podocytes, mesangium, or parietal epithelial cells with different combinations leading to proteinuria, hematuria, and azotemia. Although disease process begins in the cells of mentioned above, there is cross-talk with tubular cells leading to tubular atrophy and interstitial fibrosis in the final stages of most GN. Recent developments in genetic, molecular, serologic methods enhances understanding of the pathophysiology and management of GN although more work is needed. The recent ultra-structural studies demonstrated various subcellular disorders present in the context of GN. Mitochondria are one of the most studied subcellular organelles, and various mitochondrial structural and functional alterations have been identified in GNs, including focal segmental glomerulosclerosis, IgA nephropathy, lupus nephritis and anti-glomerular basement membrane disease. However, these studies are still at an early stage and currently the impacts of mitochondrial dysfunction on the development and progression of glomerular disease are not well defined. In the current review article, we examine how mitochondrial dysfunction associates with GN, and discuss the unknowns, conflicting issues and potential treatment options regarding mitochondrial dysfunction and GN.

Copper (Cu), an essential micronutrient and transition metal, plays a critical role in numerous biological processes, particularly within the cardiovascular system. Both cuprous (Cu⁺) and cupric (Cu²⁺) forms of copper are extensively involved in regulating key cellular biological processes, including apoptosis, autophagy, cell proliferation, mitochondrial dysfunction, inflammation, immune dysregulation, glucose/lipid metabolism and gut microbiota. Maintaining copper homeostasis is fundamental for cardiovascular health. Growing evidence indicates that copper dyshomeostasis may act as a critical trigger for the onset and progression of cardiovascular diseases (CVDs), such as atherosclerosis, stroke, hypertension, cardiac hypertrophy, heart failure, ischemia/reperfusion injury, and myocardial infarction. Accordingly, targeting copper dysregulation may offer a promising strategy for CVDs therapy. In this review, we summarize the essential functions of copper and examine how its dysregulation contributes to cellular dysfunction and the pathophysiology of CVDs. We further explore the molecular mechanisms by which copper imbalance drives CVD pathogenesis. Additionally, recent advances and current challenges in copper-targeted therapeutic strategies are discussed. By elucidating the Yin-Yang role of copper in cardiovascular biology, this review may provide a comprehensive foundation for future research and therapeutic development.

Trillions of microbes inhabit the human gut and engage in diverse biological processes by secreting different metabolites. These metabolites influence mitochondrial function and produce ROS. This gut-mitochondrial communication plays a pivotal role in regulating cellular homeostasis, energy production, and oxidative stress management, all required for optimal health. Short-chain fatty acids, secondary bile acids, amines, and gaseous metabolites are major gut metabolites that aid in governing mitochondrial processes to facilitate effective energy production and avoid oxidative damage. In the case of damaged mitochondrial function, it can alter gut flora (dysbiosis), resulting in inflammation and assisting a number of diseases such as multiple sclerosis, Alzheimer's disease, IgA nephropathy, inflammatory bowel disease, and colorectal cancer. The gut-mitochondria axis is a multifaceted interaction that regulates a cell's energy homeostasis and provides novel therapeutic opportunities. Probiotics, prebiotics, dietary modifications, and metabolite therapies have the potential to restore gut-microbe balance, enhance mitochondrial function, and reduce oxidative stress. These measures have the potential for new treatments for many diseases by modulating the gut-mitochondria axis. This review surveys interactions among gut microbiota, mitochondrial ROS, and the gut-mitochondria axis, describing how such relationships affect health and disease.

Radiotherapy is the standard adjuvant treatment for hepatocellular carcinoma (HCC). Cancer stem cells (CSCs) have been identified as the primary factor contributing to radiation resistance. Astrocyte elevated gene-1 (AEG-1) could regulate β-catenin signaling to maintain tumor stem-like stemness and self-renewal. This study aims to explore the role and mechanism of AEG-1 in the radioresistance of HCC. The mRNA levels of AEG-1 and FOXP1 were determined using RT-qPCR. AEG-1, FOXP1, Oct4, CD133, Nanog, β-catenin, and c-Myc protein levels were detected using western blot. The radiosensitivity of HCC cells was assessed using cell colony formation assay, γ-H2AX immunofluorescence, and flow cytometry. The CSC characteristics of cells were examined using sphere formation assay. The biological role of AEG-1 on HCC tumor growth and radiation resistance was examined by the mouse xenograft tumor model. Correlation between AEG-1 and FOXP1 in HCC patients was analyzed using Pearson correlation analysis. Binding between FOXP1 and AEG-1 promoter was predicted by JASPAR and verified by ChIP, the electrophoretic mobility shift assays (EMSA), and dual-luciferase reporter assays. AEG-1 was highly expressed in HCC patients, and positively associated with FOXP1 expression. Moreover, AEG-1 knockdown could enhance the radiosensitivity of HCC cells by promoting ionizing radiation (IR)-DNA damage and apoptosis in vitro. AEG-1 mediated radiation resistance by maintaining HCC tumor stem cell properties. In vivo investigation revealed that AEG-1 silencing repressed HCC tumor growth and increased radiosensitivity. Mechanistically, FOXP1 was a transcription factor of AEG-1 that promoted AEG-1 transcription by binding to its promoter region. FOXP1 promoted the Wnt/β-catenin pathway by regulating AEG-1. Overall, overexpressing FOXP1 drives stem cell properties and radioresistance of HCC cells by promoting AEG-1-mediated Wnt/β-catenin pathway, providing a promising therapeutic target for enhancing radiotherapy efficacy.

Endothelial dysfunction is a primary cause of cardiovascular complications that lead to atherosclerosis, while oxidative stress has been highligthted as one mechanism involved in endothelial dysfunction. Prevention of oxidative stress may then be a strategy to avoid endothelial dysfunction and cardiovascular disease. As the ability of oleic acid of reducing reactive oxygen species and related oxidative stress has been shown, other potential cellular mechanisms that could be responsible for the protective effect have to be evaluated. Autophagy is considered a cellular adaptive response under stressful conditions; thus, its role in the protective mechanism of oleic acid in stressed endothelial (EA.hy926) cells was assessed. To that end, cell viability and markers of oxidative status, such as reactive oxygen species, reduced glutathione, glutathione peroxidase, and reductase were evaluated. Moreover, the expression of several key autophagy-related proteins, such as microtubule-associated protein 1 light chain 3 beta and ubiquitin-binding protein p62/sequestosome 1, were investigated. The results showed that oleic acid within the micromolar range stimulated autophagy. However, when autophagy was inhibited in endothelial cells under oxidative stress, changes in the chemoprotective effect of oleic acid were minimal. These results suggest a limited contribution of autophagy to the protective effect of oleic acid under conditions of severe oxidative stress.

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.