BioFactors最新文献

Current lifestyles include calorie-dense diets and late-night food intake, which can lead to circadian misalignment. Our group recently demonstrated that sweet treats before bedtime alter the clock system in healthy rats, increasing metabolic risk factors. Therefore, we aimed to assess the impact of the sweet treat consumption time on the clock system in rats fed a cafeteria diet (CAF). Moreover, since flavanols have demonstrated beneficial effects in metabolic disorders and clock gene modulation, we also investigated whether these phenolic compounds can restore the circadian disruption caused by these altered dietary patterns. For this, 64 Fisher rats were fed CAF for 9 weeks. In the last 4 weeks, animals were daily administered a low dose of sugar (160 mg/kg) as a sweet treat at 8 a.m. (ZT0) or 8 p.m. (ZT12). Two other groups received 25 mg/kg of grape seed flavanols in addition to sweet treats. Finally, the animals were sacrificed at different time points (9 a.m., 3 p.m., 9 p.m., and 3 a.m.). The results showed that metabolic and circadian disturbances by CAF may be influenced by the time of sugar administration, slightly reinforcing the alterations in diurnal rhythmicity of serum biochemical parameters, hormones, and hypothalamic genes with bedtime snacking. Flavanols improved metabolic health and restored the oscillation of biochemical parameters, hormones, and clock and appetite-signaling genes, showing greater effects at ZT12. These results highlight the importance of meal timing in influencing physiological and metabolic outcomes, even under calorie-dense diets. Moreover, they also suggest the zeitgeber role of flavanols, modulating the clock system and contributing to an improved metabolic profile under different feeding pattern conditions.

Curcumin, a compound from Curcuma longa L., has significant anti-inflammatory properties. However, the mechanisms underlying its anti-inflammatory activity in dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) remain inadequately understood. This study aimed to further elucidate the molecular mechanisms of curcumin DSS-induced UC mice. Our data showed that curcumin alleviated DSS-induced colitis by reducing intestinal damage and inflammation, increasing goblet cells in colon tissues. Enzyme-linked immunosorbent assay revealed that curcumin reduced the expression of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1β, and interleukin-8) in serum and myeloperoxidase in colon tissues. A comprehensive analysis integrating network pharmacology and RNA sequencing (RNA-seq) revealed significant enrichment of the nuclear factor kappa B (NF-κB) signaling pathways. Notably, RNA-seq analysis demonstrated that curcumin significantly downregulated the mRNA expression of sphingosine kinase 1 (SphK1). Furthermore, molecular docking analysis showed that curcumin can bind to SphK1 and NF-κB. Additionally, curcumin was found to inhibit the activation of the SphK1/NF-κB signaling pathway in DSS-induced UC colon tissue. This study addresses pharmacologic and mechanistic perspectives of curcumin that ameliorates DSS-induced UC and inflammatory response.

Breast cancer continues to be a major health issue for women worldwide, with vimentin (VIM) identified as a crucial factor in its progression due to its role in cell migration and the epithelial-to-mesenchymal transition (EMT). This study focuses on elucidating VIM's regulatory mechanisms on the miR-615-3p/PICK1 axis. Utilizing the 4T1 breast cancer cell model, we first used RNA-seq and proteomics to investigate the changes in the APA of PICK1 following VIM knockout (KO). These high-throughput analyses aimed to uncover the underlying transcriptional and proteomic alterations associated with VIM's influence on breast cancer cells. RNA-seq and proteomic profiling revealed significant APA in PICK1 following VIM KO, suggesting a novel mechanism by which VIM regulates breast cancer progression. Validation experiments confirmed that VIM KO affects the miR-615-3p-PICK1 axis, with miR-615-3p's regulation of PICK1 being contingent upon the APA of PICK1. These findings highlight the complex interplay between VIM, miR-615-3p, and PICK1 in the regulation of breast cancer cell behavior. This study reveals that vimentin affects the miR-615-3p-PICK1 axis through APA, revealing the key role of VIM in cancer progression. Opened up new avenues for targeted cancer therapy, with a focus on regulating the interaction between APA and miR-615-3p-PICK1.

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally and is the second leading cause of cancer mortality. FAM49B, a member of the FAM49 gene family, is a recently identified, evolutionarily conserved gene. Emerging studies indicate that FAM49B plays a role in various cancers, though its specific mechanism in CRC remains largely unexplored. In this study, we observed that FAM49B was abnormally expressed in CRC tissues and cell lines, with elevated expression correlating with poor patient prognosis. FAM49B knockdown markedly suppressed CRC cell proliferation by arresting the cell cycle and reducing cell migration and invasion. Single-cell RNA-seq (ScRNA-seq) analysis revealed that high FAM49B expression in malignant epithelial cell clusters was strongly linked to c-Myc oncogene activation. Further, FAM49B knockdown significantly reduced c-Myc expression by enhancing its K48 ubiquitination. We identified NEK9 as a direct interacting partner of FAM49B, with FAM49B knockdown inhibiting NEK9-Thr210 phosphorylation. Similarly, high NEK9 expression was linked to unfavorable prognosis in CRC. In FAM49B-overexpressing CRC cells, NEK9 knockdown significantly suppressed c-Myc expression, c-Myc-ser62 phosphorylation, and reduced cell proliferation, migration, and invasion. Thus, directly targeting the FAM49B/NEK9/c-Myc pathway presents a promising therapeutic approach for c-Myc positive CRC patients.

Ultraviolet (UV) irradiation is a major factor contributing to skin photoaging, including the formation of reactive oxygen species (ROS), collagen breakdown, and overall skin damage. Insulin-like growth factor-I (IGF-1) is a polypeptide hormone that regulates dermal survival and collagen synthesis. Echinacoside (Ech), a natural phenylethanoid glycoside, is the most abundant active compound in Cistanches. However, its potential benefits for the skin and the underlying molecular mechanisms remain unclear. The objective of this research is to investigate the protective effect of Ech on human dermal fibroblast cells (HDFs) against UVB-induced skin photodamage. In this study, we demonstrated that Ech promotes IGF-1/IGF-1R/ERK-mediated collagen synthesis and IGF-1/IGF-1R/PI3K-mediated survival pathways, as well as induces IGF-1 secretion to counteract UVB-induced aging in HDFs. Furthermore, UVB-induced accumulation of SA-β-gal-positive cells, ROS, and impaired collagen synthesis were attenuated following Ech treatment. However, the protective effects of Ech were significantly diminished when IGF-1 and IGF-1R expression was silenced using small interfering RNA, indicating that Ech exerts its antiaging effects primarily by activating the IGF-1/IGF-1R signaling pathway. Our findings provide evidence of the antiaging effects of Ech on UVB-induced skin photodamage and suggest its potential development as a supplement in cosmetic dermal protective products.

Endometrial cancer (EC) is a prevalent gynecological malignancy with a rising incidence and poor prognosis in advanced cases. Long non-coding RNAs (lncRNAs) have been implicated in various cancers, including EC. This study explores the role of lncRNA Linc01224 in EC. Analyzing TCGA data, we found Linc01224 expression significantly elevated in EC tissues, correlating with poor prognosis. Clinical samples validated these findings, showing higher Linc01224 levels in tumor tissues. Knockdown of Linc01224 in EC cell lines (Hec-1-B and Ishikawa) inhibited proliferation, migration, and promoted apoptosis, alongside increased Bax and decreased BCL2 expression. Furthermore, Linc01224 knockdown notably reduced Wnt2/β-catenin pathway activation. We identified TPX2 as a target of miR-4673, which is regulated by Linc01224 through a competing endogenous RNA (ceRNA) mechanism. Dual-luciferase reporter assays confirmed miR-4673 binding to Linc01224 and TPX2. Rescue experiments revealed that TPX2 knockdown reversed Linc01224-induced proliferation and migration, highlighting TPX2's pivotal role in Linc01224's oncogenic function. In vivo, Linc01224 knockdown significantly impeded tumor growth and metastasis in a xenograft model, with decreased expression of c-Myc, Cyclin D1, and β-catenin. These findings reveal a novel ceRNA regulatory axis involving Linc01224, miR-4673, and TPX2, elucidating Linc01224's role in EC progression through the Wnt2/β-catenin pathway. Linc01224 emerges as a potential biomarker and therapeutic target for EC prognosis and treatment.

Tumor angiogenesis and the presence of cancer stem cells (CSCs) are critical characteristics of tumors. Previous research has demonstrated that cancer stem cells promote tumor angiogenesis, while increased vascularity, in turn, fosters the growth of cancer stem cells. This creates a detrimental cycle that contributes to tumor progression. However, studies investigating the angiogenesis and stemness characteristics in ovarian cancer (OV) are limited. In this study, we employed cluster analysis and LASSO methods to assess the significance of angiogenesis- and stemness-related genes in the efficacy of OV immunotherapy. Through multivariate Cox regression analysis and Friends analysis, we identified TNFSF11 as the most significant prognostic gene associated with angiogenesis and stemness. Additionally, molecular docking results confirmed that TNFSF11 exhibits a high affinity for sorafenib and sunitinib. In summary, for the first time, we conducted a comprehensive analysis of the roles of angiogenesis and stemness-related genes in the prognosis and immunotherapy of OV patients, revealing TNFSF11 as a novel therapeutic target.

Stem cells play a critical role in human tissue regeneration and repair. In addition, cancer stem cells (CSCs), subpopulations of cancer cells sharing similar characteristics as normal stem cells, are responsible for tumor metastasis and resistance to chemo- and radiotherapy and to tumor relapse. Interestingly, all stem cells have cannabinoid receptors, such as cannabidiol (CBD), that perform biological functions. The aim of this systematic review was to analyze the effect of CBD on both somatic stem cells (SSCs) and CSCs. Of the 276 articles analyzed, 38 were selected according to the inclusion and exclusion criteria. A total of 27 studied the effect of CBD on SSCs, finding that 44% focused on CBD differentiation effect and 56% on its protective activity. On the other hand, 11 articles looked at the effect of CBD on CSCs, including glioblastoma (64%), lung cancer (27%), and breast cancer (only one article). Our results showed that CBD exerted a differentiating and protective effect on SCCs. In addition, this molecule demonstrated an antiproliferative effect on some CSCs, although most of the analyses were performed in vitro. Therefore, although in vivo studies should be necessary to justify its clinical use, CBD and its receptors could be a specific target to act on both SSCs and CSCs.

Bladder cancer (BC) is the most common urinary tract malignancy. Identifying biomarkers that predict prognosis and immune function in patients with BC can enhance our understanding of its pathogenesis and provide valuable guidance for diagnosis and treatment. Our findings indicate that increased ITGB1 expression is associated with higher clinical grade and stage, establishing ITGB1 as an independent prognostic risk factor for BC. Enrichment analysis revealed that the function of ITGB1 in BC was linked to the extracellular matrix. The experimental results showed that ITGB1 knockdown in the BC cell lines 5637 and RT112 reduced their proliferation, migration, and invasion. Furthermore, ITGB1 suppression promotes apoptosis in BC cells by inhibiting the PI3K-AKT pathway. A prognostic risk model incorporating CES1, NTNG1, SETBP1, and AIFM3 was developed based on ITGB1, this model can accurately predict patient prognosis based on immunological status. In conclusion, this study shows that knockdown of ITGB1 can restrain the migratory and invasive capabilities of BC cells and accelerate apoptosis, and this role might be associated with PI3K-AKT, highlighting its potential as a diagnostic marker and therapeutic target for BC.