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TNKS1 Affects the Metabolism and Proliferation of Glioma via the PGC-1α Pathway
No full textObjective: Glioma is a primary central malignant tumor, but its curative effects and postoperative prognosis are still not ideal. Tankyrase1 (TNKS1) has been reported to promote the progression of glioma. This study aimed to assess the potential molecular mechanisms by which TNKS1 regulates the metabolism and proliferation of glioma. Methods: U87 and U251 cells with TNKS1 knockdown were established upon transfection using shRNA-TNKS1. Cell viability was detected by the Cell Counting Kit-8 (CCK-8) assay, the glucose and lactic acid levels were measured using a biochemical detection kit. While reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) levels were detected through flow cytometry. The Western blot assay was applied to check the expression levels of Akt, phosphorylated Akt (p-Akt), and glucose transporter type 1 (GLUT1). Besides, TNKS1-knockdown U87 and U251 cells were implanted to establish a nude mice xenograft model, followed by tumor growth monitoring. The apoptosis was evaluated using the Terminal-deoxynucleoitidyl transferase Mediated Nick End Labeling (TUNEL) assay and the immunohistochemical assay was applied to check the expression levels of peroxisome-proliferator-activated receptor γ coactivator (PGC)-1α, Akt, p-Akt, and GLUT1. Results: After knocking down TNKS1 in both U251 and U87 cells, the cell viability was significantly suppressed. The content of glucose, lactic acid, and PGC-1α was significantly downregulated, and the production of ROS was enhanced while the MMP level was reduced. Moreover, the Akt, p-Akt, and GLUT1 expressions were notably inhibited. The tumor growth was inhibited, and apoptosis was greatly induced in U87 and U251 xenograft tumor tissues, accompanied by the downregulation of PGC-1α, Akt, p-Akt, and GLUT1 in tumor tissues. Conclusions: Knockdown of TNKS1 could inhibit the metabolism and proliferation of glioma by mediating the PGC-1α
Efficacy Analysis of Ifosfamide Combined with MVAC to Treat Osteosarcoma
No full textObjective: To explore the curative effect of ifosfamide combined with MVAC (methotrexate, vincristine, adriamycin and cisplatin) to treat osteosarcoma. Methods: Data from patients with osteosarcoma admitted to the Second Hospital of Nanjing and the Fourth Hospital of Hebei Medical University from February 2020 to February 2021 were selected for a retrospective analysis. They were 1:1 divided in the experimental group (EG) and the control group (CG) according to the treatment method applied. The CG was given MVAC, and the EG received MVAC and ifosfamide. Short-term efficacy, inflammatory factors levels and the incidence of adverse reactions between the two groups was assessed. Results: Overall, 120 patients were included in the study. Treatment efficiency in the EG was higher than in the CG (p < 0.05). Tumor necrosis factor-α (TNF-α), c-reactive protein (CRP) and white blood cell (WBC) levels in the EG were overtly lower. Interleukin-10 (IL-10) level was significantly higher compared to the CG (all p < 0.001). Adverse reactions incidence in the EG was lower than in the CG (p < 0.05). Conclusions: Ifosfamide and MVAC combined to treat osteosarcoma show a good safety profile, with improved inflammatory factors levels
Neutrophil-Lymphocyte Ratio as an Inflammatory Biomarker in Methylamphetamine Dependence in Chinese Han
No full textObjective: Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and monocyte-lymphocyte ratio (MLR) had emerged as useful inflammatory biomarkers in multiple diseases. The study aimed to explore the possible relationships between NLR, PLR, MLR and methylamphetamine dependence, and explore their potential wider use in clinical research. Methods: 632 methylamphetamine-dependent patients and 325 controls were enrolled. The demographics, complication of dependence, and hematologic parameters were compared. The NLR, PLR, and MLR were estimated and compared between the two groups. Result: The count of white blood cell (WBC), neutrophil, monocyte, NLR, MLR, and PLR were significantly higher and the lymphocyte count was significantly lower in methylamphetamine-dependent patients than controls (p < 0.05). Multivariate analysis showed that the NLR, MLR, monocyte, and platelet were screened as useful biomarkers to evaluate the inflammatory states of methylamphetamine dependence, respectively (NLR: OR (odds ratio) = 71.72, 95% CI (confidence interval) [27.63–186.19], p < 0.001. MLR: OR = 6.34, 95% CI [3.27–12.27], p < 0.001. Monocyte: OR = 26.34, 95% CI [3.44–206.11], p = 0.002. Platelets: OR = 3.71, 95% CI [1.97–7.02], p < 0.001). However, there were no significant differences in WBC, neutrophil cell, lymphocyte, and PLR (p > 0.05). Similar results were obtained after adjusting for age and gender. The receiver operating characteristic curve (ROC) analysis indicated that the NLR and MLR were useful parameters to identify the inflammatory states of methylamphetamine dependence (AUC (area under the curve): NLR = 0.89, MLR = 0.82, platelet = 0.64, monocyte = 0.77, p < 0.001). Furthermore, the NLR was significantly and positively associated with severity of dependence scale (SDS) score and hallucination in methylamphetamine-dependent patients (p < 0.05). However, the MLR was uncorrelated with those variables (p > 0.05). Conclusions: The NLR might serve as a useful clinical biomarker in inflammatory states of methylamphetamine dependence, and positively correlated with hallucination and severity of methylamphetamine dependence
Effect of Quercetin on Adriamycin-Induced Glomerulosclerosis: A Quantification-Based Proteomics Analysis
No full textBackground: Focal segmental glomerulosclerosis is the leading cause of kidney disease worldwide. The potential effect of quercetin on glomerulosclerosis was identified using quantification-based proteomic analysis. Methods: Glomerulosclerosis was induced using adriamycin in rats treated with quercetin for 8 weeks starting on the day of adriamycin injection. Next, significant differentially expressed proteins (DEPs) were identified through label-free quantification-based proteomic analysis of renal samples. Functional analysis was performed to evaluate the effects of quercetin on glomerulosclerosis. Results: In this study, 26,431 peptides and 5272 proteins were identified using quantification-based proteomic analysis. Clusters of Orthologous Groups analysis identified general function prediction as the only key initiation factor in the glomerulosclerosis process. Gene Ontology analysis showed that these DEPs were parsed into six major components: cell, cell part, cellular process, binding organelle, single-organism process, and metabolic process. Kyoto Encyclopedia of Genes and Genomes analysis revealed 803 DEPs involved in metabolic pathways. Notably, DEPs were distributed in the PI3K-Akt signaling pathway at a proportion of 3.08%. We showed that quercetin substantially contributes to the protection against glomerulosclerosis through the extracellular region. Quercetin can also inhibit the progression of glomerulosclerosis through the PI3K/Akt pathway. Conclusions: These results suggest a novel therapeutic approach for glomerulosclerosis
Tryptase Delta 1 Gene Induces Neuropathic Pain through Activation of Microglia by NF-κB Signaling Pathway
No full textBackground: The pathogenesis of neuropathic pain (NP) remains a mystery, and no ideal treatment methods or prevention measures exist. Our goal was to identify potential therapeutic targets for NP using the RNA sequencing (RNA-Seq) dataset GSE126611 from the Gene Expression Omnibus (GEO) database and experimentally validate the potential target. Methods: Dataset GSE126611 was used for screening differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA). KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) enrichment analyses were performed on the DEGs and key modules. Tryptase delta 1 (TPSD1) was screened out for experimental validation. A chronic constriction injury (CCI) model of a rat was used to induce NP. The levels of mechanical nociceptive threshold (MNT) and thermal pain threshold (TPT) of rats were measured on days 1, 7 and 14 after modeling. On day 14, levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, IL-10, and transforming growth factor (TGF)-β in serum were measured by enzyme-linked immunosorbent assay (ELISA). Expression levels of TPSD1 in the meningeal tissue, p65 and NF-κB (nuclear factor kappa-B) inhibitor alpha (IκBα) in the spinal dorsal horn tissue were measured by quantitative PCR (qPCR) and Western blot. Immunofluorescence measured the expression of ionized calcium-binding adapter protein 1 (Iba1) in the spinal dorsal horn tissue. TPSD1 and NF-κB inhibitor BAY 11-7082 were used to induce microglia. Cell supernatant was collected for IL-1β, TNF-α, IL-6, IL-10, and TGF-β detection. Cells were collected for p65, phosphorylated p65 (p-p65), IκBα, phosphorylated IκBα (p-IκBα), Iba1, CD86, and CD206 expression levels detection. Results: In vivo results showed that compared with the sham group, the levels of MNT, TPT, TGF-β, IL-10, IκBα, and TPSD1 in the CCI group were notably down-regulated, whereas the levels of IL-1β, TNF-α, IL-6, p-IκBα, and Iba1 were obviously up-regulated. Besides, we cultured microglia with TPSD1, and results showed that compared to the conventional culture microglia, the levels of TGF-β, IL-10, p-p65, p-IκBα, and M1 marker CD86 were significantly decreased, while the levels of IL-1β, TNF-α, IL-6, IκBα, and M2 marker CD206 were significantly increased. Conclusions: The TPSD1 gene induces the activation of the NF-κB signaling pathway, which activates microglia and polarizes them toward the M1 phenotype, leading to the secretion of pro-inflammatory factors and causing pain. The findings suggest that the management of neuropathic pain could be improved by targeting TPSD1
Overexpression of MiR-140-5p can Significantly Improve IL-1β-Induced Chondrocytes Cell Viability and Inflammatory Response
No full textObjective: To investigate the biological function of the miR-140-5p/Nrf2 (nuclear factor erythroid 2-Related factor 2) axis in the development and progression of osteoarthritis. Methods: The optimal concentration of Interleukin-1β (IL-1β)-induced mouse chondrocytes ATDC-5 cells was selected by CCK-8 (cell counting kit-8), subsequent to the construction of an in vitro osteoarthritis model. Quantitative real-time polymerase chain reaction (RT-qPCR) was applied to test the transfection efficiency of ATDC-5 cells and miR-140-5p mimics. Additionally, cell apoptosis and cycle were determined by flow cytometry, cell viability was observed through CCK-8 assay, and Heme Oxygenase-1 (HO-1), Nrf2, B-cell lymphoma-2-Associated X (BAX), and B-cell lymphoma-2 (Bcl-2) protein expression levels were analyzed via western blotting. IL-6, TNF (tumor necrosis factor)-α and MDA (malonyldialdehyde) were studied by conducting ELISA (enzyme-linked immunosorbent assay);And the targeting association of Nrf2 and miR-140-5p, was by dual-luciferase reporter assay analysis. Results: The outcomes suggested that IL-1β (10 ng/mL) notably inhibited ATDC-5 cell viability. Relative to controls, Nrf2 protein expression markedly rose and miR-140-5p levels remarkably declined in ATDC-5 cells following IL-1β treatment. Dual-luciferase reporter test indicated that Nrf2 served as a miR-140-5p target gene. In addition, miR-140-5p overexpression greatly promoted IL-1β-induced ATDC-5 cell viability and inhibited ATDC-5 cell cycle arrest and apoptosis. Moreover, miR-140-5p overexpression significantly decreased Nrf2, BAX and HO-1 levels while increased Bcl-2 in IL-1β-induced ATDC-5 cells. Moreover, miR-140-5p overexpressed in ATDC-5 cells down-regulated intracellular inflammatory cytokines—MDA, IL-6 and TNF-α levels. Conclusions: Altogether, miR-140-5p may alleviate osteoarthritis by inhibiting inflammatory response, chondrocyte apoptosis, cell cycle arrest, and oxidative stress
STIL Regulated by N6-Methyladenosine Methyltransferase RBM15 can Facilitate Lung Adenocarcinoma Progression
No full textBackground: N6-methyladenosine (m6A) modification regulates gene stability, leading to the progression of lung adenocarcinoma (LUAD). However, the regulatory mechanism of the RNA-binding motif protein 15 (RBM15), an m6A methyltransferase that regulates SCL-interrupting locus protein (STIL) stability, has not yet been elucidated. This study aimed to determine the function and mechanism of action of RBM15 in LUAD. Materials and Methods: Bioinformatics analysis predicted the expression and correlation of RBM15 and STIL in LUAD. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the levels of RBM15 and STIL in clinical samples from patients with LUAD. Then, in vitro and in vivo experiments were performed to confirm the effects of RBM15 and STIL on the progression of LUAD. Finally, Methylated RNA Immunoprecipitation, mRNA stability, qRT-PCR, and western blotting were performed to identify the correlation between RBM15 and STIL in LUAD cells. Results: RBM15 was confirmed to be upregulated in LUAD, and its knockdown inhibited LUAD malignancy by decreasing proliferation, migration, and invasion. In vivo experiments confirmed that RBM15 knockdown inhibited tumor growth. RBM15 knockdown reduces STIL stability via m6A modification. Additionally, STIL overexpression contributed to the malignancy of LUAD cells; however, RBM15 knockdown partly relieved this effect. Conclusion: RBM15 knockdown suppresses LUAD progression by reducing STIL stability. This may provide novel biomarkers for the diagnosis and therapy of LUAD
LINC02381 Silencing Repressed EML4-ALK+ Lung Cancer Cell Proliferation, Migration and Invasion via miR-133b/ALK Axis
No full textBackground: Long non-coding RNAs (lncRNAs) have been intensively expounded to be implicated in various cancers, including lung cancer (LC), where LINC02381 is highly expressed in lung adenocarcinoma, but its function on LC is poorly defined. Additionally, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) functions as a prominent pathogenic factor in NSCLC, one major subtype of LC. This paper is designed to investigate whether and how LINC02381 affects EML4-ALK+ LC progression. Methods: EML4-ALK+cells were transfected with small interfering RNA (siRNA) for LINC02381 (LIN-siRNA). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was made to test ALK, miR-133b and LINC02381 expression levels. The targeting relationship between LINC02381 and miR-133b or miR-133b and ALK was predicted and verified through bioinformatics analysis and dual-luciferase reporter assay. The proliferative, migratory and invasive abilities of cells were evaluated by 5-ethynyl-2’-deoxyuridine (EdU), colony formation, wound healing and Transwell assays. Results: LINC02381 expression levels were upregulated in EML4-ALK+ LC cells. LINC02381 targeted miR-133b and miR-133b targeted ALK. LINC02381 silencing promoted miR-133b expression to down-regulate ALK levels in EML4-ALK+ LC cells. LINC02381 silencing repressed EML4-ALK+ LC cell proliferation, migration and invasion. Conclusions: LINC02381 silencing inhibits EML4-ALK+ LC cell proliferation, migration and invasion via the miR-133b/ALK axis
MicroRNA-526b-3p and Wnt/β-catenin Pathways Regulate Programmed Death Ligand 1 to Inhibit Growth and Migration of Gefitinib-Resistant Lung Adenocarcinoma Cells
No full textBackground: Lung cancer is a malignant tumor that seriously threatens human life and health. Gefitinib is a first-line treatment for epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD), but drug resistance is a major obstacle limiting its efficacy. This work aims to examine the effect and underlying mechanism of programmed death ligand 1 (PD-L1) on gefitinib-resistant LUAD cell growth and migration. Methods: Bioinformatics prediction was utilized to predict the targeted binding microRNAs (miRNAs) of PD-L1, after which further verification was performed through dual-luciferase reporter assay and quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Transfection of gefitinib-resistant cells was completed with PD-L1 overexpression plasmid and miR-526b-3p mimic. XAV-939, an inhibitor of Wnt/β-catenin, was also used to treat gefitinib-resistant cells. Measurement of β-catenin and PD-L1 protein levels were performed using Western blotting. Cellular biological behaviors were determined using relative functional assays. Results: miR-526b-3p directly targeted PD-L1, and miR-526b-3p level was lower in gefitinib-resistant cells gefitinib-resistant HCC827 (HCC827GR) and gefitinib-resistant PC9 (PC9GR) than in sensitive cell lines HCC827 (containing EGFR deletion from E746 to A750; CC-Y1188) and PC9 (containing EGFR exon 19 deletion; CC-Y1418) (p < 0.001). Moreover, miR-526b-3p mimic reduced gefitinib-resistant cell viability, proliferation, migration and invasion, while PD-L1 up-regulation offset the roles of miR-526b-3p mimic (p < 0.05). XAV-939 diminished PD-L1 and β-catenin levels, and suppressed gefitinib-resistant cellular biological behaviors, which further enhanced the inhibitory effects of miR-526b-3p mimic (p < 0.05). Conclusions: miR-526b-3p and Wnt/β-catenin pathways regulate PD-L1, thereby inhibiting the growth, invasion and migration of gefitinib-resistant LUAD cells
Cytoprotective and Anti-Oxidative Stress Capacity of South American Medicinal Plant Brunfelsia grandiflora in Endothelial Cells
No full textBackground: Oxidative stress is a potential cause of cardiovascular pathologies, so the protection of endothelial cells and vascular tissues is essential to avoid such conditions, perhaps with the use of natural compounds rich in phenolic compounds with a proven high antioxidant capacity. The present study was designed to show the cytoprotective capacity of phenolic extracts from the plant Brunfelsia grandiflora, as well as describe its antioxidant defense mechanisms and the expression of some molecular markers involved in cellular protection. Methods: Human EA.hy926 cells were exposed to Brunfelsia grandiflora (B. grandiflora) extract (1, 10, 25, 50, 100, and 200 μg/mL) in co-treatment (22 h with 100 μM tert-Butyl hydroperoxide (t-BOOH) and B. grandiflora concentrations) and pre-treatment (18 h of B. grandiflora concentrations and then 200 μM t-BOOH for 4 h). Cell viability, reactive oxygen species (ROS) production, nitric oxide (NO) levels, caspase 3/7 activity, malondialdehyde (MDA) concentration, and reduction in reduced glutathione (GSH) levels, glutathione peroxidase (GPx), and glutathione reductase (GR) activity were measured, and real-time PCR molecular assays superoxide dismutase (SOD2), nuclear factor E2-related factor (NRF2), BCL-2-associated X protein (BAX), and B-cell lymphoma 2 (BCL2) were performed. Data were analyzed via one-way ANOVA followed by Tukeys post hoc test. Results: B. grandiflora bark extract, mainly at concentrations of 25, 50, 100, and 200 μg/mL, significantly (p < 0.05) reversed (pre-treatment and co-treatment) the deleterious effects of t-BOOH on EA.hy926 endothelial cells, which were significantly decreased cell viability, GSH activity, and SOD2 and NRF2 expression (p < 0.05); and significantly increased levels of ROS, NO, MDA, caspase-3/7 activity, GPx activity, GR activity, and the BAX/BCL2 ratio (p < 0.05). Conclusions: B. grandiflora extract was able to reduce the deleterious effects of t-BOOH on EA.hy926 endothelial cells, which may indicate its potential phytotherapeutic benefit against cytotoxic damage caused by chemical agents