Biomolecules & biomedicine最新文献

Cervical cancer presents a significant healthcare challenge due to recurrent disease and drug resistance, highlighting the urgent need for novel therapeutic strategies. Network pharmacology facilitates drug repurposing by elucidating multi-target mechanisms of action. Adefovir, an acyclic nucleotide analog, has shown promising potential in cervical cancer treatment, particularly in HeLa cells. In vitro studies have demonstrated that adefovir inhibits HeLa cell proliferation by enhancing apoptosis while maintaining a low cytotoxicity profile at therapeutic concentrations, making it an attractive candidate for further exploration. A combined network pharmacology and in vitro study was conducted to investigate the molecular mechanism of adefovir against cervical cancer. Potential gene targets for adefovir and cervical cancer were predicted using database analysis. Hub targets were identified, and protein-protein interaction (PPI) networks were constructed. Molecular docking assessed adefovir's binding affinity to key targets. In vitro cytotoxic assays, including 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet assays, were performed using 96-well plates to evaluate anti-proliferative effects in HeLa cells. Apoptosis was assessed via p53 immunocytochemistry Enzyme-Linked Immunosorbent Assay (ELISA), while Vascular Endothelial Growth Factor ELISA (VEGF ELISA) was used to measure cell proliferation. Venn analysis identified 144 common targets between adefovir and cervical cancer. Network analysis revealed key hub targets involved in oncogenic pathways. Molecular docking demonstrated strong binding between adefovir and Mitogen-Activated Protein Kinase 3 (MAPK3) and SRC proteins. In vitro, adefovir significantly suppressed HeLa cell viability, with an Inhibitory Concentration 50 (IC50) of 7.8 μM, outperforming 5-Fluorouracil (5-FU). Additionally, it induced apoptosis via p53 activation and inhibited cell proliferation through VEGF suppression. These integrated computational and experimental findings suggest that adefovir exerts multi-targeted effects against cervical cancer. Its promising preclinical efficacy warrants further investigation as a potential alternative therapy.

Differentiating early-stage breast cancer from benign breast masses is crucial for radiologists. Additionally, accurately assessing axillary lymph node metastasis (ALNM) plays a significant role in clinical management and prognosis for breast cancer patients. Chest computed tomography (CT) is a commonly used imaging modality in physical and preoperative evaluations. This study aims to develop a deep learning model based on chest CT imaging to improve the preliminary assessment of breast lesions, potentially reducing the need for costly follow-up procedures such as magnetic resonance imaging (MRI) or positron emission tomography-CT and alleviating the financial and emotional burden on patients. We retrospectively collected chest CT images from 482 patients with breast masses, classifying them as benign (n = 224) or malignant (n = 258) based on pathological findings. The malignant group was further categorized into ALNM-positive (n = 91) and ALNM-negative (n = 167) subgroups. Patients were randomly divided into training, validation, and test sets in an 8:1:1 ratio, with the test set excluded from model development. All patients underwent non-contrast chest CT before surgery. After preprocessing the images through cropping, scaling, and standardization, we applied ResNet-34, ResNet-50, and ResNet-101 architectures to differentiate between benign and malignant masses and to assess ALNM. Model performance was evaluated using sensitivity, specificity, accuracy, receiver operating characteristic (ROC) curves, and the area under the curve (AUC). The ResNet models effectively distinguished benign from malignant masses, with ResNet-101 achieving the highest performance (AUC: 0.964; 95% CI: 0.948-0.981). It also demonstrated excellent predictive capability for ALNM (AUC: 0.951; 95% CI: 0.926-0.975). In conclusion, these deep learning models show strong diagnostic potential for both breast mass classification and ALNM prediction, offering a valuable tool for improving clinical decision-making.

Cancer therapy-related cardiac dysfunction (CTRCD) is a major concern for patients undergoing cardiotoxic cancer treatments. Sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown cardioprotective effects in both diabetic and non-diabetic populations. However, their impact on CTRCD risk remains uncertain. This meta-analysis aimed to assess the association between SGLT2 inhibitor use and CTRCD in cancer patients receiving cardiotoxic treatments. A systematic search of PubMed, Embase, and Web of Science was conducted to identify relevant studies. Cohort studies comparing CTRCD incidence in cancer patients with and without SGLT2 inhibitor use were included. Risk ratios (RRs) were pooled using a random-effects model, and subgroup and meta-regression analyses were performed to explore potential effect modifiers. Ten cohort studies involving 34,847 cancer patients met the inclusion criteria. Overall, SGLT2 inhibitor use was associated with a significantly reduced risk of CTRCD (RR: 0.47, 95% confidence interval: 0.33-0.68, P < 0.001), though significant heterogeneity was observed (I² = 70%). Subgroup analysis indicated a stronger protective effect in patients receiving anthracyclines (RR: 0.26) compared to those undergoing other treatments (RR: 0.73, P for subgroup difference = 0.001). Additionally, the cardioprotective effect was more pronounced in cohorts with a lower proportion of men (<55%, RR: 0.27) compared to those with a higher proportion (≥55%, RR: 0.75, P < 0.001). Sensitivity analyses, conducted by excluding one study at a time, consistently supported these findings, reinforcing their robustness. In conclusion, SGLT2 inhibitor use is associated with a lower risk of CTRCD in cancer patients, particularly those receiving anthracyclines. These findings highlight the potential role of SGLT2 inhibitors in mitigating cardiotoxicity during cancer therapy.

Invasive pulmonary aspergillosis (IPA) is the most frequent invasive fungal disease occurring in patients with hematological malignancies. Serum galactomannan (GM) antigen monitoring is thought to be helpful in the diagnosis of IPA. The aim of this study was to determine the role of a GM assay in serum samples for the diagnosis of IPA in patients with hematological disease. The data of 366 immunosuppressed patients that were hospitalized and followed up in the hematology clinic from January 2017 to December 2019 were retrospectively analyzed. The clinical and radiological findings of the patients and the GM results, requested twice a week, were evaluated. In this study, the incidence of probable and possible IPA was determined to be 15.3% (56/366). Of the cases detected, 28 (50.0%) were patients diagnosed with acute myeloid leukemia (AML), and 34 (60.7%) patients who had compatible clinical and examination findings were started on antifungal treatment. Additionally, area under the curve (AUC) values were calculated by receiver operating characteristic (ROC) analysis, and it was determined that the diagnostic efficiency was more predictive when the cut-off was 0.5 in the GM test for IPA disease. The detection of GM antigen in serum is a very useful and rapid method for diagnosing IPA disease in immunosuppressed hematology patients. However, GM results should be evaluated together with clinical and radiological findings for early diagnosis, and the treatment approach should be determined accordingly.

One of the most prominent causes of alopecia areata (AA) is chronic inflammation of the hair follicles. Inhibiting cellular pyroptosis, a form of inflammatory programmed cell death, is crucial for reducing follicular inflammation in the skin. Total glucosides of paeony (TGP) possess anti-inflammatory properties across a broad range of illnesses. However, the role of TGP in AA and its relationship to pyroptosis remain unclear. A chronic unpredictable mild stress (CUMS) approach was used to create an AA mouse model. TGP suspension and MCC950 were administered to AA mice via gavage. HE staining, ELISA, immunohistochemistry, immunofluorescence, RT-qPCR, and Western blotting were performed to detect pathological changes in the skin and investigate the levels of inflammatory factors and pyroptosis-related proteins, as well as the potential mechanisms of TGP's effects. TGP reduced hair loss, increased the number of hair follicles in skin tissues, and decreased inflammatory markers (IL-6, TNF-α, IL-18, and IL-1β) in AA mice. MCC950 significantly reduced the levels of NLRP3/caspase-1/Gasdermin D (GSDMD)-mediated pyroptosis-related proteins (NLRP3, ASC, caspase-1 p10, and GSDMD-N), as well as inflammatory factors. TGP markedly inhibited NLRP3/caspase-1/GSDMD-mediated cellular pyroptosis in a concentration-dependent manner. TGP suppresses the NLRP3/caspase-1/GSDMD signaling cascade in the skin tissues of AA mice, thereby reducing cellular pyroptosis and inflammation. TGP may be a potential therapeutic agent for AA.

The C6orf120 gene is a novel gene whose function has not been fully defined. Previous studies have associated it with various liver pathologies, but its specific role in hepatocellular carcinoma (LIHC) remains unclear. This study aimed to investigate the diagnostic and prognostic value of C6orf120 in LIHC, as well as its potential biological functions. In this preliminary research, we utilized data from various databases and bioinformatics tools, including TCGA, GEO, TIMER2, HPA, GEPIA, Linkeomics, Metascape, CIBERSORT, TargetScan, DIANA-microT, RNAinter, and ENCORI, to analyze the expression patterns and mechanisms of C6orf120 in LIHC. Our bioinformatics analysis revealed that C6orf120 is upregulated in LIHC and may serve as a diagnostic and prognostic biomarker. The aberrant expression of C6orf120 in LIHC was further supported by clinical samples and cell lines. In vitro experiments demonstrated that the knockdown of C6orf120 in HepG2 cells significantly reduced migration capacity without affecting proliferation. Additionally, the downregulation of C6orf120 in LIHC cells appeared to inhibit endothelial cell migration and angiogenesis, which are critical in tumorigenesis and development. In conclusion, our findings suggest that C6orf120 could serve as a novel diagnostic and prognostic biomarker for LIHC and is expected to be a prognostic marker and a potential therapeutic target in the clinical management of LIHC.

Cell death has long been a focal point in life sciences research, and recently, scientists have discovered a novel form of cell death induced by copper, termed cuproptosis. This paper aimed to identify genes associated with cuproptosis in systemic lupus erythematosus (SLE) through machine learning, combined with single-cell RNA sequencing (scRNA-seq), to screen and validate related genes. The analytical results were then experimentally verified. Two published microarray gene expression datasets (GSE65391 and GSE61635) from SLE and control peripheral blood samples were downloaded from the GEO database. The GSE65391 dataset was used as the training group, while the GSE61635 dataset served as the validation group. Differentially expressed genes from GSE65391 identified 12 differential genes. Nine diagnostic genes, considered potential biomarkers, were selected using the least absolute shrinkage and selection operator and support vector machine recursive feature elimination analysis. The receiver operating characteristic (ROC) curves for both the training and validation groups were used to calculate the area under the curve to assess discriminatory properties. CIBERSORT was used to assess the relationship between these diagnostic genes and a reference set of infiltrating immune cells. scRNA-seq data (GSE162577) from SLE patients were also obtained from the GEO database and analyzed. Experimental validation of the most important SLE biomarkers was performed. Twelve significantly different cuproptosis-related genes were identified in the GSE65391 training set. Immune cell analysis revealed 12 immune cell types and identified nine signature genes, including PDHB, glutaminase (GLS), DLAT, LIAS, MTF1, DLST, DLD, LIPT1, and FDX1. In the GSE61635 validation set, seven genes were weakly expressed, and two genes were strongly expressed in the treatment group. According to the ROC curves, PDHB and GLS demonstrated significant diagnostic value. Additionally, correlation analysis was conducted on the nine characteristic genes in relation to immune infiltration. The distribution of key genes in immune cells was determined using scRNA-seq data. Finally, the mRNA expression of the nine diagnostic genes was validated using qPCR.

Polyamidoamine (PAMAM) dendrimer nanoparticles are efficient drug delivery vectors with potential clinical applications in nanomedicine. However, PAMAMs can compromise heart function, and strategies to mitigate cardiotoxicity would be beneficial. In this study, we investigated whether the adjunct use of three key cardioprotective agents could prevent cardiac injury induced by a seventh-generation cationic PAMAM dendrimer (G7). Isolated rat hearts were subjected to ischemia and reperfusion (I/R) injury in the presence or absence of G7 or the cardioprotective agents Losartan, epidermal growth factor (EGF), or S-nitroso-N-acetylpenicillamine (SNAP). I/R injury significantly compromised cardiac function, in terms of left ventricular (LV) hemodynamics, contractility, and vascular dynamics, which were markedly improved (P < 0.05) by the administration of Losartan, EGF, or SNAP alone, confirming their cardioprotective effects. The administration of G7 significantly worsened cardiac function recovery following I/R (P < 0.05). G7-induced impairments in cardiac and vascular dynamics were significantly improved by co-administration of Losartan, EGF, or SNAP. Treatment with G7 also significantly increased cardiac enzyme levels and infarct size, both of which were markedly reduced upon co-infusion of Losartan, EGF, or SNAP (P < 0.05). Thus, G7 deteriorates the recovery of cardiac function in isolated hearts subjected to I/R injury, which can be rescued by co-administration of Losartan, EGF, or SNAP. These findings enhance our understanding of PAMAM dendrimer nanotoxicology in the mammalian heart and suggest that the adjunct use of cardioprotective agents is an effective strategy for mitigating the cardiotoxicity of these dendrimers and potentially other drug delivery systems.

This study explored the mechanism by which forkhead box O-1 (FoxO1) modulates the biological behaviors of bone mesenchymal stem cell (BMSC). Human BMSCs were cultured for seven days in Dulbecco's modified Eagle medium (DMEM) containing bone morphogenetic protein-2 (BMP-2) and treated with a short hairpin-FoxO1 plasmid. The study assessed cell proliferation, migration, apoptosis, adenosine triphosphate (ATP) levels, mitochondrial DNA (mtDNA) levels, membrane potential (MMP), autophagy, and the levels of FoxO1, apoptosis-associated proteins, osteogenic differentiation-associated proteins, mitochondrial fusion and fission proteins, and mitochondrial autophagy-related proteins. The cells were also treated with the mitochondrial fusion activator MASM7 and the mitochondrial autophagy activator carbonyl cyanide 3-chlorophenylhydrazone (CCCP). The study evaluated whether mitochondrial dynamics and autophagy activation could rescue the FoxO1 knockdown-induced changes in BMSC biological behaviors, mitochondrial dynamics, and mitochondrial autophagy. BMP-2-induced BMSCs exhibited upregulated FoxO1 expression, enhanced proliferation and migration, and induced osteogenic differentiation, while FoxO1 knockdown inhibited BMP-2-induced BMSC proliferation, migration and osteogenic differentiation, increased apoptosis, and affected mitochondrial dynamics and autophagy. Promoting mitochondrial fusion partially reversed the regulatory effects of FoxO1 downregulation on mitochondrial autophagy and the inhibitory effects of FoxO1 silencing on BMP-2-induced BMSC biological behaviors. Activated mitochondrial autophagy facilitated the homeostasis of mitochondrial dynamics and partially counteracted the inhibitory effects of FoxO1 knockdown on BMP-2-induced BMSC biological behaviors. In conclusion, FoxO1 regulates mitochondrial dynamics and autophagy to modulate the osteogenic differentiation of BMP-2-induced human BMSCs.

Circular RNA (circRNA) has been proven to be a key regulator in a range of tumor illnesses, such as lung adenocarcinoma (LUAD); however, the regulatory mechanisms of circRNA remain unclear. In this study, circRNA (hsa_circ_0001492) in LUAD was examined for its regulatory and functional potential. qRT-PCR was used to assess the hsa_circ_0001492 level in LUAD. The RNAse R digestion test was employed to isolate hsa_circ_0001492. The primary location of hsa_circ_0001492 enrichment in LUAD cells was identified through a nucleoplasmic separation test. LUAD cell migration, proliferation, and spherogenicity were examined using wound healing, transwell, EdU, and cell spherogenicity assays. The association between miR-145-5p and hsa_circ_0001492/ovarian carcinoma immunoreactive antigen domain 2 (OCIAD2) was validated using a dual luciferase experiment. The interaction between sh-hsa_circ_0001492 and miR-145-5p was confirmed through an RNA pull-down assay. The effects of hsa_circ_0001492, miR-145-5p, and OCIAD2 on LUAD tumor development were examined using xenograft mouse models and immunohistochemistry tests. Results showed a higher amount of hsa_circ_0001492 in LUAD. The cytoplasm of LUAD cells was observed in the area where hsa_circ_0001492 mainly accumulated; hsa_circ_0001492 enhanced LUAD cell migration, proliferation, and sphere-forming ability. MiR-145-5p and OCIAD2 were identified as targets of hsa_circ_0001492 and miR-145-5p, respectively. The level of OCIAD2 was increased by hsa_circ_0001492 through targeted binding to miR-145-5p. In nude mice, tumor growth was inhibited by silencing hsa_circ_0001492, while knockdown of miR-145-5p and overexpression of OCIAD2 promoted the growth of LUAD tumors. In conclusion, hsa_circ_0001492 regulates the hsa-miR-145-5p/OCIAD2 axis to promote the progression of LUAD, and could be a useful target for the diagnosis and treatment of LUAD.