International Journal of Molecular and Cellular Medicine最新文献

Glioblastoma (GBM) is the most aggressive and lethal brain tumor. Artificial neural networks (ANNs) have the potential to make accurate predictions and improve decision making. The aim of this study was to create an ANN model to predict 15-month survival in GBM patients according to gene expression databases. Genomic data of GBM were downloaded from the CGGA, TCGA, MYO, and CPTAC. Logistic regression (LR) and ANN model were used. Age, gender, IDH wild-type/mutant and the 31 most important genes from our previous study, were determined as input factors for the established ANN model. 15-month survival time was used to evaluate the results. The normalized importance scores of each covariate were calculated using the selected ANN model. The area under a receiver operating characteristic (ROC) curve (AUC), Hosmer-Lemeshow (H-L) statistic and accuracy of prediction were measured to evaluate the two models. SPSS 26 was utilized. A total of 551 patients (61% male, mean age 55.5 ± 13.3 years) patients were divided into training, testing, and validation datasets of 441, 55 and 55 patients, respectively. The main candidate genes found were: FN1, ICAM1, MYD88, IL10, and CCL2 with the ANN model; and MMP9, MYD88, and CDK4 with LR model. The AUCs were 0.71 for the LR and 0.81 for the ANN analysis. Compared to the LR model, the ANN model showed better results: Accuracy rate, 83.3 %; H-L statistic, 6.5 %; and AUC, 0.81 % of patients. The findings show that ANNs can accurately predict the 15-month survival in GBM patients and contribute to precise medical treatment.

Chronic lymphocytic leukemia (CLL) is the most prevalent hematological cancer, with various medical interventions. In the recent decade, cold physical plasma has become an interesting agent for future cancer therapy. The goal of this study was to see whether cold physical plasma or cold physical plasma-treated liquid (PTL) affected integrin beta 3 (ITGB3) expression, which is hypothesized to mediate an interaction between cancer stem cells and the bone marrow microenvironment, in CLL patients' blood cells. The metabolic activity, cell death pattern, lipid oxidation and ITGB3 gene expression of these treatments was evaluated. Both direct cold physical plasma and PTL exposure enhanced lipid peroxidation in cells of CLL patients, but to a lesser extent in healthy participants. Furthermore, following 48h of cold physical plasma or PTL exposure, the metabolic activity of leukocytes was preferentially reduced in CLL patient leukocytes. In addition, cold physical plasma and PTL treatment elevated ITGB3 mRNA expression in CLL patients' leukocytes compared to untreated and healthy controls. Collectively, our study suggests selective effects of direct cold physical plasma and PTL exposure on blood leukocytes from leukemia patients, but further and more detailed studies are needed to provide additional rationales for such treatment options as future therapy.

Breast cancer, characterized by genetic diversity and molecular subtypes, presents significant treatment challenges, especially in human epidermal growth factor receptor type 2 (HER2)-positive cases, which are associated with poor prognosis. Metformin, widely known for its antidiabetic effects, has emerged as a promising candidate for cancer therapy. This study investigates the effect of metformin on miR-125a promoter methylation and its subsequent impact on the HER2 signaling pathway in HER2-positive breast cancer cells (SK-BR3). SK-BR3 cells were cultured and treated with various concentrations of metformin to assess its effects on cell viability, DNA methylation, HER2, and DNA Methyltransferase 1 (DNMT1) expression. Molecular analyses focus on the miR-125a signaling pathway modulation, DNA methylation, mRNA expression of DNMT1, and protein level of HER2. Research showed a dose-dependent reduction in cell viability, with IC50 values from 65 mM at 48 hours to 35 mM at 72 hours. Metformin treatment led to demethylation of the miR-125a promoter, which increased miR-125a expression and subsequently reduced HER2 levels. This suggests that metformin exerts its anticancer effects partly by regulation of the miR-125a-HER2 axis. Additionally, metformin inhibited vimentin expression, indicating its potential to interfere with epithelial-mesenchymal transition (EMT) processes. Metformin may serve as a targeted therapeutic agent in HER2-positive breast cancer by modulating the miR-125a-HER2 axis and influencing on the epigenetic and EMT regulation. Further research is warranted to elucidate the therapeutic potential of metformin through these mechanisms.

Colorectal cancer is one of the most serious malignancies affecting humans. In this study, Streptomyces bioactive chemicals extracted from soil were analyzed for their anti-colorectal-cancer and antibacterial properties. A total of 100 soil samples were collected from Kerman-Iran, incubated in SCA media and the antimicrobial properties were tested using the cross-streak method. Three strains were cultured in ISP4 medium to obtain secondary bioactive compounds. After studying the effects of the bioactive compounds on the HT29 and human foreskin fibroblast (HFF) cell lines, the expression of the p53, p21, BAX, BCL2, Casp3 and Casp8 genes was analyzed by real-time PCR and flow cytometry to detect the presence of apoptosis.The isolates show high degree of identification with Streptomyces rochei, Streptomyces fungicidicus and Streptomyces maritimus due to 16SrDNA sequence homology. Compared to HT-29 cells, Streptomyces extracts had lower cytotoxicity against normal cells (SI=5.88), followed by HFF (SI=4.14). The cell lines demonstrated a dose-dependent significant increase in DNA fragmentation, an increase in the proportion of cells in sub-G1 phase and caused G2/M cell cycle arrest in HT-29 and HFF cells.The bacterial extracts obtained displayed strong antibacterial properties and inhibited the proliferation of HT-29 and HFF cell lines. The treated cells exhibited morphological changes caused by the activation of caspase and p53/p21 proteins. This confirms that Streptomyces-induced apoptosis is mediated by the activation of p21/p53. Anti-apoptotic Bcl-2 gene expression was downregulated by treatment with the extracts. Further studies are needed to understand the antimicrobial properties of Streptomyces.

Coronary Slow Flow (CSF) is observed in individuals who experience delayed blood supply in the coronary arteries. Inflammation and endothelial dysfunction may play a role in the etiology and development of CSF. The current investigation aimed to compare the expression of specific long noncoding RNAs (lncRNAs) associated with endothelial dysfunction and inflammation in CSF patients. This case‒control study enrolled 72 CSF patients and 71 healthy individuals. Blood samples were collected, and serum marker levels were measured. The expression levels of lncRNAs ANRIL, MALAT1, and LINC00305 in peripheral blood mononuclear cells (PBMCs) were assessed using real-time Polymerase Chain Reaction (PCR). All statistical analyses were performed using SPSS 22, with the significance level set at P < 0.05. The study revealed that the relative expression of MALAT1 and LINC00305 was significantly lower in the CSF group (p < 0.01), whereas ANRIL was expressed at higher levels (p < 0.0001). The areas under the ROC curves (AUCs) for MALAT1, LINC00305, and ANRIL were 0.64, 0.66, and 0.75, respectively. Notably, the expression level of LINC00305 exhibited an inverse correlation with CSF incidence (OR: 0.83, p: 0.008) in contrast to that of ANRIL (OR: 1.43, p < 0.0001). Additionally, compared to those in the control group, the average BMI, WBC, RBC, Hb, LDH, LDL, FBS, and percentage of neutrophils in the CSF group were significantly greater (p< 0.05). lncRNA ANRIL is upregulated in CSF patients, whereas MALAT1 and LINC00305 are downregulated. Dysregulation of ANRIL, MALAT1, and LINC00305 may serve as diagnostic and predictive factors for CSF leakage.

Rosemary is an aromatic plant with ancient and modern applications as a spice and herbal remedy. Due to the strong antioxidant potential of rosemary, the present study investigated the anti-proliferative and pro-apoptotic characteristics of rosemary on luminal A and triple-negative breast cancer cells. The effect of rosemary extract on the WNT10B and β-Catenin genes was also evaluated. The WNT10B and β-Catenin expression were measured by real-time PCR. The outcomes of the MTT assay and AnnexinV/PI flow cytometry assay showed that exposure of MCF-7 and MDA-MB-231 cells to rosemary reduced cell viability in a dose-time-dependent routine and promoted apoptosis in breast cancer cells. It was revealed that the extract could exert cytotoxic and apoptotic effects by downregulation of WNT10B and β-Catenin. Our results suggest rosemary as a promising complementary herbal medicine for breast cancers, without the adverse effects of chemotherapy drugs.

Treatment failure after intravesical instillation of Bacillus Calmette-Guerin immunotherapy (BCG) for non-muscle-invasive bladder cancer (BCa) occurs frequently. The exact effects of BCG on cellular redox status and gene expression remain unclear. We assessed oxidative stress biomarkers and changes in miR-155-5p expression in response to BCG. Twenty-seven patients with BCa were recruited for measuring tissue and serum malondialdehyde (MDA) and total antioxidant capacity (TAC) levels, and tissue expression of miR-155-5p at two-time points: pre and 6 weeks post BCG. Recurrence of BCa was observed after 20 months. R statistical software was used for paired comparisons of biomarkers, as well as the correlation between variables. Significant increases in TAC were observed after BCG (P= <0.001). Tissue MDA levels were significantly reduced (P= 0.003). miR-155-5p was slightly overexpressed after BCG (median fold change=1.3, P=0.25). At the 20-month follow-up, it was observed that improved MDA and TAC changes were significant only in patients without recurrence of BCa. In patients with recurrence, the pre-treatment expression ratio of miR-155-p5 was positively correlated with TAC (R=0.63, P= 0.032) and negatively correlated with MDA (R=-0.72, P=0.037). In patients with recurrence of BCa pre-treatment miR-155-5p showed negative correlation with its expression changes after BCG (R=-0.78, P=0.004). Conclusions: Treatment with BCG has some beneficial effects on the oxidative stress status, which is probably modulated by miR-155-5p. A well-controlled oxidative balance may enhance overall survival of BCa. Considering its high recurrence rate, our pilot experiment can open a window toward better management of patients with BCa.

Overexpression of (myeloid leukemia cell differentiation protein 1) Mcl-1 is associated with the reduction of ABT-737 toxicity and secondary resistance. In this study, the effect of formononetin (biochanin B) on Mcl-1 expression, cell growth, apoptosis, and ABT-737 sensitivity of the acute lymphoblastic leukemia (ALL) cells was investigated. In this experimental study, the cell proliferation and MTT assays were used to investigate the effect of formononetin on cell growth and survival. qRT-PCR was performed for the measurement of gene expression. Hoechst 33342 staining and caspase-3 activity assay were used for the determination of apoptosis. Our data showed that formononetin and ABT-737 both led to a significant reduction in the IC₅₀ value and synergistically reduced the cell growth and survival relative to single treatment. Overexpression of Mcl-1 was found after the treatment with ABT-737. Formononetin decreased the expression of B-cell lymphoma 2 (Bcl-2) and Mcl-1 and increased the Bcl-2-associated protein x (Bax) and P21 expression. Moreover, formononetin enhanced the apoptotic effect of ABT-737 in ALL cells. In summary, formononetin showed anti-carcinogenic activities in human ALL cells via suppression of cell growth and survival. Formononetin enhanced the apoptotic effect of ABT-737, with contribution by inhibition of the Mcl-1 expression.

Transforming growth factor beta (TGF-β) initiates epithelial-mesenchymal transition (EMT) in tubular and glomerular epithelial cells, resulting in excessive production and deposition of extracellular matrix through its interaction with TGF-β receptors, which play a crucial role in TGF-β signaling involving two receptor types, namely TGF-β type I (TβRI) and type II (TβRII). EMT contributes to the pathogenesis of interstitial renal fibrosis, a marker of end-stage kidney disease. This study aimed to identify the bioactive compounds in the active fraction of P. angulata and evaluate their ability to inhibit the TGF-β activity and their potential as drug candidates. The active components in the active fraction of P. angulata were analyzed using gas chromatography-mass spectrometry (GC-MS). The bioactive compound structures were obtained from the PubChem database, while the protein targets, TβRI and TβRII, were retrieved from the Protein Data Bank (PDB). The molecular docking analyses were performed using PyRx 0.8 and Discovery Studio. SwissADME was used to evaluate ligand properties and druglikeness. Three dominant active compounds were identified, namely palmitic acid, campesterol, and stigmasterol. In silico studies demonstrated strong energy bonds existed between TβRI and palmitic acid, campesterol, stigmasterol, and SB431542 with binding energy values of -5.7, -10, -9.4, and -10.9 kcal/mol, respectively. Similarly, they strongly bound to TβRII with binding energy values of -5.2, -7.1, -7.5, and -6.1 kcal/mol, respectively. All compounds meet Lipinski's criteria for druglikeness. Among the identified active compounds, campesterol exhibited the highest affinity for TβRI, while stigmasterol exhibited a strong affinity for TβRII. These findings suggested that the three compounds have potential as drug candidates.

One of the burning issues facing healthcare organizations is multidrug-resistant (MDR) bacteria. P. aeruginosa is an MDR opportunistic bacterium responsible for nosocomial and fatal infections in immunosuppressed individuals. According to previous studies, efflux pump activity and biofilm formation are the most common resistance mechanisms in P. aeruginosa. The aim of this study was to propose new antimicrobial peptides (AMPs) that target P. aeruginosa and can effectively address these resistance mechanisms through in silico and in vitro assessments. Since AMPs are an attractive alternative to antibiotics, in vitro experiments were carried out along with bioinformatics analyses on 19 Nef peptides (derived from the HIV-1 Nef protein) in the current study. Several servers, including Dbaasps, Antibp2, CLASSAMP2, ToxinPred, dPABBs and ProtParam were used to predict Nef peptides as AMPs. To evaluate the binding affinities, a molecular docking analysis was performed with the HADDOCK web server for all Nef peptide models against two effective proteins of P. aeruginosa (MexB and PqsR) that play a role in efflux and quorum sensing. Moreover, the antibacterial and antibiofilm activity of the Nef peptides was investigated in a resistant strain of P. aeruginosa. The results of molecular docking revealed that all Nef peptides have a significant binding affinity to the abovementioned proteins. Nef-Peptide-19 has the highest affinity to the active sites of MexB and PqsR with the HADDOCK scores of -136.1 ± 1.7 and -129.4 ± 2, respectively. According to the results of in vitro evaluation, Nef peptide 19 showed remarked activity against P. aeruginosa with minimum inhibitory and bactericidal concen-trations (MIC and MBC) of 10 µM and 20 µM, respectively. In addition, biofilm inhibitory activity was observed at a concentration of 20 µM. Finally, Nef peptide 19 is proposed as a new AMP against P. aeruginosa.