BioFactors最新文献

Cancerous transcriptome alterations in carcinoma cells could be originated from either genetic copy number changes or epigenetic reprogramming. Ovarian cancer (OV) is the most malignant gynecologic tumor, known for high aneuploidy with robust copy number alterations. However, low aneuploidy ovarian tumors are also frequently found, indicating an essential contribution of epigenetic factors during tumorigenesis and cancer development. Chromatin remodeling modulates the transcriptome epigenetically in a variety of cancer types, but its role in OV is still unclear. Hence, we investigated a cohort of 102 OV patients, analyzed transcriptomic and clinical data from public databases, and performed cellular experiments. We found that RUVBL2, a subunit of the INO80 complex, functions as the key oncogenic chromatin remodeler in OV. RUVBL2 is upregulated in tumors, particularly in low-aneuploidy cases, and is associated with poor prognosis. RUVBL2 drives nucleosome dynamics and elevates chromatin accessibility selectively at promoter regions. The landscape of RUVBL2-dependent modulation of chromatin accessibility and the transcriptome exhibits activation of various transcription factors, especially the AP-1 family, and upregulation of a series of key genes, including CDKN3, MYBL2, and ZNF144, resulting in mediation of cell cycle and Hippo signaling pathway to promote DNA synthesis and cell proliferation. Hence, RUVBL2-dependent chromatin remodeling plays a key role in oncogenic reprogramming of the transcriptome in OV. These findings provide novel insights into the molecular etiology of OV and disclose potential biomarkers and drug targets.

Crohn's disease (CD), a chronic inflammatory bowel disorder, is driven by dysregulated interactions between gut microbiota and host metabolism. Here, we developed a computational framework integrating multiomics profiling, network pharmacology, and molecular dynamics simulations to systematically map microbiota-metabolite-target-signaling (M-M-T-S) networks and identify therapeutic candidates. By analyzing gut microbial metabolomics and CD-associated targets (via SwissTargetPrediction [STP]/SEA), we constructed a protein–protein interaction (PPI) network enriched for 50 intestinal hub targets (IL6, AKT1, PPARG; degree centrality [CD] > 19.4), which orchestrate inflammatory (TNF/IL-17/TLR, FDR = 3.8 × 10⁻¹²) and metabolic (PPAR, FDR = 1.5 × 10⁻¹⁰) pathways. Structure-based screening (AutoDock Vina/AMBER20) revealed 3-indolepropionic acid (IPA) as a high-affinity AKT1 binder (ΔG = −67.4 kJ/mol), while Genipin exhibited robust binding to PTGS2, both validated by 100-ns dynamics simulations (RMSD < 3.8 Å). Mechanistic network analysis uncovered a dual-axis regulatory paradigm: a pro-inflammatory axis (Clostridiumspp.-derived LPS aggravates Th17 polarization via TLR4/IL-17 signaling) and a reparative axis (Faecalibacterium prausnitzii-produced butyrate enhances barrier integrity through PPARγ-mediated NF-κB suppression). Phylogenetic analysis linked microbial functional traits (e.g., LPS/SCFA synthesis) to evolutionary conservation, highlighting clade-specific roles in CD progression. Drug-likeness evaluation (SwissADME/ADMETlab 2.0) prioritized IPA as a lead candidate due to its superior solubility (7.65 mg/mL), nonhepatotoxic profile, and AhR agonism, outperforming Genipin. This study establishes IL6/AKT1/PPARG as central therapeutic hubs and positions IPA for clinical translation. Our framework bridges multiomics integration with precision medicine, offering a scalable strategy to decode microbiome-driven pathologies and accelerate metabolite-based therapeutics.

Ferroptosis, a newly discovered non-apoptotic form of cell death triggered by iron-dependent toxic membrane lipid peroxidation, establishes a link between redox biology, metabolism, and human health. By inducing ferroptosis, it is possible to selectively eliminate cancer cells and cancer stem cells (CSCs) that are resistant to traditional therapies. Recent research has shown that inducing ferroptosis can effectively kill colorectal cancer stem cells (CRC CSCs) that are resistant to other forms of cell death and treatment modalities, positioning it as a potentially innovative strategy for developing treatments for colorectal cancer. This review delves into the intricate molecular mechanisms underlying ferroptosis in colorectal CSCs, focusing on the specific pathways and signaling networks that regulate ferroptotic cell death in these cells, including the roles of iron metabolism, lipid peroxidation, amino acid metabolism, and antioxidant systems. Additionally, we explored the application of ferroptosis-associated genes for the early diagnosis and prognosis of CRC and also discuss ferroptosis inducers as anticancer agents, highlighting their potential to effectively target therapy-resistant CSCs by disrupting their redox balance and triggering lipid peroxidation. Last, we discuss potential challenges and directions for future research in this developing area, offering insights into future studies pertaining to ferroptosis in CRC treatment.

Nitrosative stress plays a key role in the etiology of several human diseases, such as atherosclerosis, inflammation, cancer, and neurological diseases. Peroxynitrite is one of the most potent biological nitrosative agents, being produced at extremely rapid rates when nitric oxide (^●NO) and superoxide (^●O₂⁻) are combined. Peroxynitrite undergoes self-degradation at a slow rate, yielding ~70% nitrate (NO₃⁻) and H⁺, and ~30% nitrite (NO₂⁻) and dioxygen (O₂). Peroxynitrite degradation can be speeded up by the interaction with either (i) carbon dioxide (CO₂), through the transient formation of 1-carboxylato-2-nitrosodioxidane adduct (ONOOC(O)O⁻), which eventually decays to CO₂ and NO₃⁻ via the intermediate strong oxidants trioxocarbonate (CO₃^●−) and (nitrogen dioxide) ^●NO₂⁻, and/or (ii) proteins, such as thiol peroxidases and heme-proteins by different mechanisms. Under physiological conditions, peroxynitrite detoxification, which brings about different effects on the cellular metabolism, depends on the relative concentration of CO₂ and proteins. In this review, we analyze the intrinsic parameters of processes involved in peroxynitrite scavenging, which are crucial in poorly oxygenated tissues (such as the retina), exploring conditions that alternatively favor one process or the other.

Browning of white adipose tissue offers a promising strategy to manage obesity by enhancing thermogenesis and lipid oxidation. Although fucosterol, a phytosterol found in brown seaweeds, has been recognized for its antioxidant and metabolic benefits, its ability to trigger browning has not been previously reported. In this study, we demonstrate for the first time that fucosterol induces adipocyte browning in 3T3-L1 cells. Treatment with fucosterol (10–50 μM) during adipogenic differentiation suppressed lipid accumulation and downregulated adipogenic transcription factors (PPARγ, C/EBPα, SREBP-1), while enhancing lipolysis via increased phosphorylation of HSL and AMPK. Critically, browning markers PRDM16, PGC1α, and UCP1 were robustly upregulated in a dose-dependent manner. Fucosterol also activated the Nrf2/HO-1 antioxidant pathway, as evidenced by increased HO-1 expression and Nrf2 nuclear translocation. Pharmacological inhibition of HO-1 or AMPK reversed these effects, confirming their essential role in fucosterol-induced thermogenic remodeling. Interestingly, despite activation of p38 and ERK MAPKs—often linked to stress signaling—fucosterol reduced pro-inflammatory cytokine levels (IL-6, IL-1β, TNF-α) and elevated antioxidant enzymes (SOD, GPx, CAT), suggesting a non-inflammatory metabolic adaptation. These findings reveal a previously uncharacterized function of fucosterol in promoting adipocyte browning, driven by HO-1/Nrf2 and AMPK pathways, with potential relevance for therapeutic strategies targeting obesity.

The debate over the impact of extensive palm oil consumption on human health, driven by its economic affordability, persists due to its high saturated fat content and potential health risks. Conversely, its diverse bioactive compounds offer antioxidant and anti-inflammatory properties. This study seeks to investigate the effects of prolonged palm oil consumption on hypothalamic insulin signaling, inflammation, and oxidative stress markers. Rats were fed either standard chow or a palm oil-enriched diet (POD) for 21 weeks, with the latter diet prepared by soaking standard briquette food in commercially available palm oil. The palm oil used in our study contained slightly more oleic acid than palmitic acid (44.3% and 39.5%, respectively). Prolonged consumption of a diet enriched with 20% of palm oil resulted in obesity in rats, accompanied by concurrent changes in blood lipid content. Additionally, palm oil consumption induced hyperinsulinemia and hyperglycemia, indicating the presence of peripheral insulin resistance. Despite these findings, our study did not reveal differences in hypothalamic insulin resistance between obese and control rats. In the cerebrospinal fluid, insulin concentration remained consistent after palm oil consumption, while glucose levels increased. Hypothalamic gene expression analysis did not show significant changes in the levels of NF-κB, IL-6, IL-1β, and Nrf2 mRNA. Moreover, the activation of insulin receptor and its substrate IRS1, as well as the expression of glucose transporters GLUT1-4 in the rat hypothalamus, remained unaltered. Ex vivo EPR spectroscopy of the obese rat hypothalamus indicated no variations in the total redox status compared to control rats. In summary, our results suggest that long-term consumption of palm oil rich in oleic acid induces obesity but does not significantly impact hypothalamic insulin expression and response, inflammation, or oxidative stress, which at least in part may be attributed to the specific fatty acid composition of the palm oil used. However, the potential contribution of other phytochemicals and bioactive compounds, such as vitamin E, must not be overlooked when interpreting the overall metabolic response to the prolonged palm oil intake.