ABSTRACT
With the inappropriate use of antibiotics, antibiotic resistance has emerged as a major dilemma for patients infected with Pseudomonas aeruginosa. Elastase B (LasB), a crucial extracellular virulence factor secreted by P. aeruginosa, has been identified as a key target for antivirulence therapy. Quercetin, a natural flavonoid, exhibits promising potential as an antivirulence agent. We aim to evaluate the impact of quercetin on P. aeruginosa LasB and elucidate the underlying mechanism. Molecular docking and molecular dynamics simulation revealed a rather favorable intermolecular interaction between quercetin and LasB. At the sub-MICs of ≤256 µg/ml, quercetin was found to effectively inhibit the production and activity of LasB elastase, as well as downregulate the transcription level of the lasB gene in both PAO1 and clinical strains of P. aeruginosa. Through correlation analysis, significant positive correlations were shown between the virulence gene lasB and the QS system regulatory genes lasI, lasR, rhlI, and rhlR in clinical strains of P. aeruginosa. Then, we found the lasB gene expression and LasB activity were significantly deficient in PAO1 ΔlasI and ΔlasIΔrhlI mutants. In addition, quercetin significantly downregulated the expression levels of regulated genes lasI, lasR, rhlI, rhlR, pqsA, and pqsR as well as effectively attenuated the synthesis of signaling molecules 3-oxo-C12-HSL and C4-HSL in the QS system of PAO1. Quercetin was also able to compete with the natural ligands OdDHL, BHL, and PQS for binding to the receptor proteins LasR, RhlR, and PqsR, respectively, resulting in the formation of more stabilized complexes. Taken together, quercetin exhibits enormous potential in combating LasB production and activity by disrupting the QS system of P. aeruginosa in vitro, thereby offering an alternative approach for the antivirulence therapy of P. aeruginosa infections. KEY POINTS: ⢠Quercetin diminished the content and activity of LasB elastase of P. aeruginosa. ⢠Quercetin inhibited the QS system activity of P. aeruginosa. ⢠Quercetin acted on LasB based on the QS system.
Subject(s)
Pseudomonas aeruginosa , Quercetin , Humans , Quercetin/pharmacology , Virulence , Pseudomonas aeruginosa/genetics , Molecular Docking Simulation , Pancreatic ElastaseABSTRACT
Skin aging is characterized by the disruption of skin homeostasis and impaired skin injury repair. Treatment of aging skin has long been limited by the unclear intervention targets and delivery techniques. Engineering extracellular vesicles (EVs) as an upgraded version of natural EVs holds great potential in regenerative medicine. In this study, we found that the expression of the critical antioxidant and detoxification gene Gstm2 was significantly reduced in aging skin. Thus, we constructed the skin primary fibroblasts-derived EVs encapsulating Gstm2 mRNA (EVsGstm2), and found that EVsGstm2 could significantly improve skin homeostasis and accelerate wound healing in aged mice. Mechanistically, we found that EVsGstm2 alleviated oxidative stress damage of aging dermal fibroblasts by modulating mitochondrial oxidative phosphorylation, and promoted dermal fibroblasts to regulate skin epidermal cell function by paracrine secretion of Nascent Polypeptide-Associated Complex Alpha subunit (NACA). Furthermore, we confirmed that NACA is a novel skin epidermal cell protective molecule that regulates skin epidermal cell turnover through the ROS-ERK-ETS-Cyclin D pathway. Our findings demonstrate the feasibility and efficacy of EVs-mediated delivery of Gstm2 for aged skin treatment and unveil novel roles of GSTM2 and NACA for improving aging skin.
Subject(s)
Extracellular Vesicles , Fibroblasts , Glutathione Transferase , RNA, Messenger , Skin Aging , Wound Healing , Animals , Mice , Fibroblasts/metabolism , Glutathione Transferase/metabolism , Extracellular Vesicles/metabolism , RNA, Messenger/metabolism , RNA, Messenger/genetics , Epidermis/metabolism , Mice, Inbred C57BL , Oxidative Stress , Skin/metabolism , Male , Humans , Epidermal Cells/metabolism , Cells, CulturedABSTRACT
BACKGROUND This study aimed to evaluate the epidemiology of osteoarthritis in China in a comprehensive and reliable way, to project its future epidemiological patterns, and to mitigate its health hazards. MATERIAL AND METHODS Data were extracted and analyzed from the Global Burden of Diseases Study 2019. Trends in osteoarthritis epidemiology were explored using joinpoint regression analysis. Additionally, we analyzed dynamic trends using the sociodemographic index (SDI) of China. To assess and predict the epidemiology of osteoarthritis from 2020 to 2039, we used both the Bayesian age-period-cohort model and Nordpred model. RESULTS The number of prevalent cases, incident cases, and years lived with disability (YLDs) for osteoarthritis in China increased from 51.8, 4.6, and 1.8 million, respectively, in 1990, to 132.8, 10.7, and 4.7 million, respectively, in 2019, and the average annual percentage changes were 3.286, 2.938, and 3.324, respectively. The prevalence and YLDs peaked in the population aged over 90 years old, while the incidence peaked in the population aged around 50 years old. A significant positive correlation was found between osteoarthritis burden and SDI. Osteoarthritis burden is expected to continue to increase. In the population studied here, it was higher in women than in men, but this may invert by 2039. CONCLUSIONS The prevalence, incidence, and YLDs of osteoarthritis had significantly increased and may continue to increase during the next 2 decades. Prevention and treatment strategies should target women, middle-aged individuals, and the elderly.
Subject(s)
Global Burden of Disease , Osteoarthritis , Aged , Male , Middle Aged , Humans , Female , Aged, 80 and over , Bayes Theorem , Prevalence , Osteoarthritis/epidemiology , Incidence , China/epidemiology , Global HealthABSTRACT
Background: Infectious bone defect refers to severe bone tissue damage caused by skeletal infection, often resulting in impaired skeletal function and intense inflammatory responses. Treating infectious bone defects is a challenging task, as conventional treatment methods often fail to completely eliminate the infection focus and may easily lead to inflammatory responses in the bone defect area. Objective: To examine the impacts of bone transport (BT) in conjunction with drug-loaded calcium sulfate (DLCS) on the expression of inflammatory factors and vascular endothelial growth factor (VEGF) in rats with infectious bone defects. Methods: A total of 40 rats were randomly allocated to 4 groups-the sham, model, BT, and BT + DLCS groups-with 10 rats in each group. Interleukin 10 (IL-10), tumor necrosis factor (TNF), nuclear factor-κB (NF-κB), insulinlike growth factor 1 (IGF 1), and recombinant human basic fibroblast growth factor (rhbFGF) concentrations in serum were measured using enzyme-linked immunosorbent assay. In bone tissue, histopathological changes in defective bone were assessed through hematoxylin-eosin staining, CD34 expression was examined by immunohistochemistry, and VEGF expression was examined by Western blot. Results: In comparison with the sham group, the model group had significant increases in serum IL-10, TNF, and NF-κB concentrations as well as notable decreases in IGF-1 and rhbFGF serum concentrations and CD34 and VEGF expression in the bone tissue (P < .05). In contrast to the model group, both the BT and BT + DLCS groups had significant reductions in serum concentrations of IL-10, TNF, and NF-κB. Additionally, the BT and BT + DLCS groups had significant increases in serum concentrations of IGF-1 and rhbFGF as well as expression of CD34 and VEGF in the bone tissue (P < .05). The BT + DLCS group had significantly lower serum concentrations of IL-10, TNF, and NF-κB compared with the BT group. Furthermore, the BT + DLCS group had significantly elevated serum concentrations of IGF-1 and rhbFGF as well as increased expression of CD34 and VEGF in the bone tissue compared with the BT group (P < .05). Conclusion: The promotion of infected bone defect healing in rats through the combination of BT and DLCS may be attributed to the suppression of inflammatory responses and the elevation of VEGF expression to facilitate vascular regeneration.
ABSTRACT
Cr (VI) is extremely harmful to both the environment and human health, and it can linger in the environment for a very long period. In this research, the Leersia hexandra Swartz constructed wetland-microbial fuel cell (CW-MFC) system was constructed to purify Cr (VI) wastewater. By comparing with the constructed wetland (CW) system, the system electricity generation, pollutants removal, Cr enrichment, and morphological transformation of the system were discussed. The results demonstrated that the L. hexandra CW-MFC system promoted removal of pollutants and production of electricity of the system. The maximum voltage of the system was 499â¯mV, the COD and Cr (VI) removal efficiency was 93.73% and 97.00%. At the same time, it enhanced the substrate and L. hexandra ability to absorb Cr and change it morphologically transformation. Additionally, the results of XPS and XANES showed that the majority of the Cr in the L. hexandra and substrate was present as Cr (III). In the L. hexandra CW-MFC system, Geobacter also functioned as the primary metal catabolic reducing and electrogenic bacteria. As a result, L. hexandra CW-MFC system possesses the added benefit of removing Cr (VI) while producing energy compared to the traditional CW system.
Subject(s)
Bioelectric Energy Sources , Chromium , Wastewater , Water Pollutants, Chemical , Wetlands , Wastewater/chemistry , Waste Disposal, Fluid/methods , Biodegradation, Environmental , Hydrocharitaceae , Geobacter/metabolism , ElectricityABSTRACT
The escalating prevalence of carbapenem-resistant Pseudomonas aeruginosa (CRPA) poses a significant threat to global public health through the spread of its 'high-risk' clones. Immediate and decisive research into antimicrobial agents against CRPA is crucial for the development of effective measures and interventions. Overexpression of the MexAB-OprM efflux pump is one of the major mechanisms of CRPA. Since the active efflux of antibacterial agents plays a significant role in mediating drug resistance in CRPA, the inhibition of efflux pumps has become a promising strategy to restore antibacterial potency. Piperine (PIP) has been proven to be a promising efflux pump inhibitor in some bacteria. However, there are no studies on whether PIP can act as a potential efflux pump inhibitor in CRPA. The present study aimed to identify the antibacterial activity of PIP against CRPA and to evaluate the effect on the MexAB-OprM efflux pump. Molecular docking was used to analyze the possible interaction of PIP with the proteins of the MexAB-OprM efflux pump in CRPA. The effect of PIP on the expression of the MexAB-OprM efflux pump was investigated by real-time quantitative PCR (qPCR) and ethidium bromide accumulation efflux assay. The effect of PIP on CRPA imipenem (IPM) resistance was investigated by the checkerboard dilution method. The results demonstrated that PIP exhibited the lowest binding affinity of -9.1 kcal towards efflux pump proteins. A synergistic effect between PIP and IPM on CRPA was observed. More importantly, PIP effectively hindered the efflux of ethidium bromide and IPM by up-regulating MexR gene expression while down-regulating MexA, MexB, and OprM gene expressions. In conclusion, PIP could enhance the antibacterial activity of IPM by inhibiting the MexAB-OprM efflux pump. Our work proved that PIP had the potential to be an efflux pump inhibitor of CRPA.
Subject(s)
Imipenem , Pseudomonas aeruginosa , Imipenem/pharmacology , Bacterial Outer Membrane Proteins/genetics , Bacterial Outer Membrane Proteins/metabolism , Ethidium/pharmacology , Molecular Docking Simulation , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/metabolism , Microbial Sensitivity TestsABSTRACT
BACKGROUND Osteoporosis is a systemic chronic disease characterized by bone mineral density (BMD) reduction. This study aimed to assess the prevalence of osteoporosis and fracture risks in northwestern China and investigate the related anthropometric risk factors. MATERIAL AND METHODS Between July 2022 and August 2022, 1429 participants (1295 females, 134 males) with measured BMD were recruited to participate in this cross-sectional study. Data on height, weight, and T score were collected. Spearman's correlation and multiple linear regression analysis were used to investigate the relationships between various demographic factors and BMD and the 10-year risk of major osteoporotic fracture (MO) and hip fracture (HP). RESULTS The overall prevalence of osteoporosis in northwest China was 42.34%, with 44.56% in females and 20.90% in males. Age negatively affects females' T scores (r=-0.304, P<0.05), and height positively influences both sexes' T scores (r=0.059 P<0.05). Age (r=0.148, P<0.05) and height were positive predictors of MO (r=0.027, P<0.05), while weight was a negative predictor (r=-0.035, P<0.05). The conclusion for HP was consistent with that of MO, except for the T score, which was a positive predictor of HP (r=0.014, P<0.05). CONCLUSIONS The prevalence of osteoporosis in northeast China is high. The association between anthropometric parameters and osteoporosis in adults in northwest China is different between sexes.
Subject(s)
Osteoporosis , Osteoporotic Fractures , Adult , Male , Female , Humans , Cross-Sectional Studies , Prevalence , Osteoporosis/epidemiology , Bone Density , China/epidemiology , Risk Factors , Absorptiometry, PhotonABSTRACT
The surface plasmon resonance (SPR) effect of noble nanometals can be utilized to effectively improve the catalytic performance of semiconductor photocatalysts. In this work, a novel composite photocatalyst of BiOBr microspheres simultaneously decorated by Ag and Bi dual nanoparticles (NPs) has been successfully synthesized by the hydrothermal method plus one-step reduction method. And the morphology, structure, chemical composition and photoelectrical properties of this composite photocatalyst (Ag/Bi-BiOBr) were further characterized. Due to the SPR effect of Ag and Bi dual NPs, Ag/Bi-BiOBr showed the high light absorption with narrow band gap, as well as fast charge separation via metal-semiconductor heterojunction so as to realize an efficient degradation of ibuprofen (IBP) under simulated solar irradiation. Through the further optimization of the loading amounts of Ag and Bi dual NPs, the excellent photocatalytic activity in the Ag/Bi-BiOBr has been achieved that 92.3% of IBP was removed within 60 min, which is among the best results reported so far for IBP degradation via photocatalysis.
Subject(s)
Ibuprofen , Nanoparticles , Bismuth/chemistry , Catalysis , LightABSTRACT
BACKGROUND: Hepatitis B virus (HBV) infection is one of the main leading causes of hepatocellular carcinoma (HCC) worldwide. However, it remains uncertain how the reverse-transcriptase (rt) gene contributes to HCC progression. METHODS: We enrolled a total of 307 patients with chronic hepatitis B (CHB) and 237 with HBV-related HCC from 13 medical centers. Sequence features comprised multidimensional attributes of rt nucleic acid and rt/s amino acid sequences. Machine-learning models were used to establish HCC predictive algorithms. Model performances were tested in the training and independent validation cohorts using receiver operating characteristic curves and calibration plots. RESULTS: A random forest (RF) model based on combined metrics (10 features) demonstrated the best predictive performances in both cross and independent validation (AUC, 0.96; accuracy, 0.90), irrespective of HBV genotypes and sequencing depth. Moreover, HCC risk scores for individuals obtained from the RF model (AUC, 0.966; 95% confidence interval, .922-.989) outperformed α-fetoprotein (0.713; .632-.784) in distinguishing between patients with HCC and those with CHB. CONCLUSIONS: Our study provides evidence for the first time that HBV rt sequences contain vital HBV quasispecies features in predicting HCC. Integrating deep sequencing with feature extraction and machine-learning models benefits the longitudinal surveillance of CHB and HCC risk assessment.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis B virus , Hepatitis B, Chronic , Liver Neoplasms , Quasispecies , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/virology , Hepatitis B virus/genetics , High-Throughput Nucleotide Sequencing , Humans , Liver Neoplasms/diagnosis , Liver Neoplasms/virology , Machine Learning , RNA-Directed DNA PolymeraseABSTRACT
BACKGROUND: As circular RNAs (circRNAs) have been found to significantly involve in the onset and progression of multiple malignant tumors including breast cancer (BC), this study aims at evaluating the diagnostic and prognostic values of circRNAs in this malady. METHODS: Available databases were thoroughly searched to collect studies on the diagnosis and/or prognosis of BC using circRNA profiling. The updated Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool and the Newcastle Ottawa Scale (NOS) were used to assess the underlying bias of included studies. Clinical characteristics of the studies were merged by the quantitative-weighted integral method to obtain the combined effects. RESULTS: Sixteen studies were included, comprising 2438 BC cases and 271 noncancerous controls. The expression signature covered 24 circRNAs (down-regulated: circ-VRK1, hsa_circ_0068033, hsa_circ_103110, hsa_circ_104689, and hsa_circ_104821; up-regulated: circAGFG1, hsa_circ_0001785, hsa_circ_0108942, hsa_circ_0001785, hsa_circ_006054, hsa_circ_100219, hsa_circ_406697, circEPSTI1, circANKS1B, circGFRA1, circ_0103552, CDR1-AS, has_circ_001569, hsa_circ_001783, circFBXL5, circ_0005230, circAGFG1, circ-UBAP2, and circ_0006528). The sensitivity and specificity of circRNAs in distinguishing BC patients from noncancerous controls were 0.65 and 0.68, and the corresponding area under the curve was 0.66. Survival analysis revealed that patients showing highly expressed oncogenic circRNAs were associated with increased mortality risks of BC in overall survival (univariate analysis: hazard ratio [HR] = 3.30, P = .000; multivariate analysis: HR = 3.07, P = .000), and disease-free survival (HR = 8.26, P = .000). Stratified analysis based on circRNA expression status and control type also showed robust results. CONCLUSIONS: Circular RNA profiling presents prominent diagnostic and prognostic values in BC, and can be rated as a promising tool facilitating its early diagnosis and survival.
Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/mortality , RNA, Circular/blood , Databases, Factual , Female , Humans , Prognosis , Sensitivity and SpecificityABSTRACT
BACKGROUND: Hemarthrosis after anterior cruciate ligament (ACL) reconstruction can create many adverse joint effects. Tranexamic acid (TXA) can be used to minimize hemarthrosis and associated pain after ACL reconstruction. We aimed to compare the efficacies of intravenous (IV) administration and intra-articular (IA) injection of TXA during ACL reconstruction for reducing postoperative hemarthrosis. METHODS: A total of 120 patients who underwent arthroscopic ACL reconstruction were included in this prospective and randomized study. All patients were randomized into three groups: IV group, IA group and placebo group. Patients in the IV group received intravenously administered TXA (15 mg/kg in 100 mL of saline solution) 10 min before tourniquet release; patients in the IA group received intra-articular TXA (15 mg/kg in 100 mL of saline solution) injected via the drainage tube; and patients in the placebo group received an equivalent volume of normal saline administered into the knee joint cavity and intravenously. Drainage tubes were removed 24 h after surgery, and all enrolled patients experienced a 4-week follow-up period. The drain output volume, visual analogue scale (VAS) score, patellar circumference, hemarthrosis grade and Lysholm score of all patients were recorded. RESULTS: Both the IV group and the IA group had significantly lower drain output volumes at day 1, lower VAS scores at weeks 1 and 2, smaller patellar circumferences at weeks 1 and 2, and lower hemarthrosis grades at weeks 1 and 2 than the placebo group (p < 0.05). There were no significant differences in drain output volume, VAS score, patellar circumference or hemarthrosis grade between the IV group and the IA group at any time point (p > 0.05). No obvious differences in Lysholm score were observed between any pair of groups at week 4 (p > 0.05)). Neither infection nor deep vein thrombosis occurred in any group. CONCLUSIONS: Both intravenous administration and intra-articular injection can reduce intra-articular hemarthrosis, joint pain and swelling during ACL reconstruction. No significant difference in the efficacies of reducing hemarthrosis, joint pain and swelling was found between intravenous administration and intra-articular injection. TRIAL REGISTRATION: The study was registered by the Chinese Clinical Trial Registry (The comparative efficacies of intravenous administration and intra-articular injection of tranexamic acid during anterior cruciate ligament reconstruction; ChiCTR-INR-17012217 ; August 1, 2017).
Subject(s)
Anterior Cruciate Ligament Injuries , Anterior Cruciate Ligament Reconstruction , Tranexamic Acid , Administration, Intravenous , Anterior Cruciate Ligament Injuries/diagnosis , Anterior Cruciate Ligament Injuries/surgery , Anterior Cruciate Ligament Reconstruction/adverse effects , Hemarthrosis/diagnosis , Hemarthrosis/etiology , Hemarthrosis/prevention & control , Humans , Injections, Intra-Articular , Prospective Studies , Tranexamic Acid/adverse effectsABSTRACT
CONTEXT: Peucedanol is a major extract of Peucedanum japonicum Thunb. (Apiaceae) roots, which is a commonly used herb in paediatrics. Its interaction with cytochrome P450 enzymes (CYP450s) would lead to adverse effects or even failure of therapy. OBJECTIVE: The interaction between peucedanol and CYP450s was investigated. MATERIALS AND METHODS: Peucedanol (0, 2.5, 5, 10, 25, 50, and 100 µM) was incubated with eight human liver CYP isoforms (CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1), in pooled human liver microsomes (HLMs) for 30 min with specific inhibitors as positive controls and untreated HLMs as negative controls. The enzyme kinetics and time-dependent study (0, 5, 10, 15, and 30 min) were performed to obtain corresponding parameters in vitro. RESULTS: Peucedanol significantly inhibited the activity of CYP1A2, 2D6, and 3A4 in a dose-dependent manner with IC50 values of 6.03, 13.57, and 7.58 µM, respectively. Peucedanol served as a non-competitive inhibitor of CYP3A4 with a Ki value of 4.07 µM and a competitive inhibitor of CYP1A2 and 2D6 with a Ki values of 3.39 and 6.77 µM, respectively. Moreover, the inhibition of CYP3A4 was time-dependent with the Ki/Kinact value of 5.44/0.046 min/µM. DISCUSSION AND CONCLUSIONS: In vitro inhibitory effect of peucedanol on the activity of CYP1A2, 2A6, and 3A4 was reported in this study. As these CYPs are involved in the metabolism of various drugs, these results implied potential drug-drug interactions between peucedanol and drugs metabolized by CYP1A2, 2D6, and 3A4, which needs further in vivo validation.
Subject(s)
Apiaceae , Chromans , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System , Plant Extracts , Humans , Apiaceae/chemistry , Cytochrome P-450 Enzyme Inhibitors/administration & dosage , Cytochrome P-450 Enzyme Inhibitors/isolation & purification , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Cytochrome P-450 Enzyme System/drug effects , Cytochrome P-450 Enzyme System/metabolism , Dose-Response Relationship, Drug , Inhibitory Concentration 50 , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Plant Extracts/administration & dosage , Plant Extracts/pharmacology , Time Factors , Chromans/administration & dosage , Chromans/pharmacologyABSTRACT
CONTEXT: Peimine and paeoniflorin can be combined for the treatment of cough in paediatrics. The interaction during the co-administration could dramatically affect the bioavailability of drugs. OBJECTIVE: The interaction between peimine and paeoniflorin was investigated in this study. MATERIALS AND METHODS: The pharmacokinetics of paeoniflorin (20 mg/kg) with or without the coadministration of peimine (5 mg/kg for 10 days before paeoniflorin) was orally investigated in Sprague-Dawley rats (n = 6). The group without the peimine was set as the control group. The metabolic stability of paeoniflorin was studied in rat liver with microsomes. The effect of peimine on the absorption of paeoniflorin was investigated with Caco-2 cell monolayers. RESULTS: The Cmax (244.98 ± 10.95 vs. 139.18 ± 15.14 µg/L) and AUC(0-t) (3295.92 ± 263.02 vs. 139.18 ± 15.14 h·µg/L) of paeoniflorin was increased by peimine. The t1/2 was prolonged from 5.33 ± 1.65 to 14.21 ± 4.97 h and the clearance was decreased from 15.43 ± 1.75 to 4.12 ± 0.57 L/h/kg. Consistently, peimine increased the metabolic stability of paeoniflorin with rat liver microsomes with the increased t1/2 (56.78 ± 2.62 vs. 26.33 ± 3.15 min) and the decreased intrinsic clearance (24.42 ± 3.78 vs. 52.64 ± 4.47 µL/min/mg protein). Moreover, the transportation of paeoniflorin was also inhibited by peimine as the efflux ratio decreased from 3.06 to 1.63. DISCUSSION AND CONCLUSIONS: Peimine increased the systemic exposure of paeoniflorin through inhibiting the activity of CYP3A4 and P-gp. These results provide a reference for further in vivo studies in a broader population.
Subject(s)
Cevanes/pharmacology , Glucosides/pharmacokinetics , Microsomes, Liver/metabolism , Monoterpenes/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Area Under Curve , Caco-2 Cells , Cevanes/administration & dosage , Cytochrome P-450 CYP3A/metabolism , Drug Interactions , Glucosides/administration & dosage , Half-Life , Humans , Male , Monoterpenes/administration & dosage , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Cancer/testis antigen (CTA) is a class of antigen molecules expressed only in the germinal epithelium of testis and some tumor tissues. As an important CTA molecule, the expression of F-box protein 39 (FBXO39) in breast cancer (BC) and its clinical significance remain unclear. The objective of this study is to explore the value of FBXO39 in the diagnosis, efficacy monitoring, and prognostic evaluation of BC. METHODS: The expression of FBXO39 mRNA in the serum exosomes of patients with BC before and after the initial diagnosis and treatment was detected by qRT-PCR, and the corresponding ROC curve was plotted. The expression of FBXO39 protein in BC cancer tissues was detected by immunohistochemistry, along with the analysis of the correlation between FBXO39 expression and clinical pathological features as well as prognosis of BC cases. RESULTS: The serum-derived exosomes were successfully isolated and identified. The positive rate of FBXO39 mRNA in serum exosomes of patients with BC was up to 86%; there was a correlation between the expression level of serum exosomal FBXO39 and clinical staging, HER2, and Ki-67 expression (all with p < 0.05). The sensitivity of serum exosomal FBXO39 in distinguishing BC patients from healthy controls was 88%, with the specificity as 86%, and AUC as 0.9432. The expression change of FBXO39 in serum-sourced exosomes of patients with BC was related to their treatment situation, indicating that the level of FBXO39 decreased significantly after treatment. The expression of FBXO39 in cancer tissue was related to the clinical stage (p = 0.023) and lymphatic metastasis (p = 0.015) of the BC patients. Survival analysis showed that the expression of FBXO39 was negatively correlated with the prognosis of BC patients, with the high expression of FBXO39 indicating poor prognosis. CONCLUSIONS: Serum-derived exosomal FBXO39 could serve as an important indicator of BC diagnosis and efficacy evaluation; FBXO39 could be rated as an important indicator of BC prognosis evaluation.
Subject(s)
Breast Neoplasms , Exosomes , F-Box Proteins , Biomarkers, Tumor/genetics , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , F-Box Proteins/genetics , Humans , Male , Prognosis , TestisABSTRACT
Diabetes can impair osteoblastic functions and negatively interfere with osteointegration at the bone/implant interface. Previously, we prepared a nanosized calcium silicate (CS) incorporated-polyetheretherketone (PK) biocomposite (CS/PK) and found that the CS/PK composite exhibited enhanced osteoblast functions in vitro and osteointegration in vivo, but its bioperformance under diabetic conditions remained elusive. In this study, MC3T3-E1 cells incubated on CS/PK and PK samples were subjected to diabetic serum (DS) and normal serum (NS); cell attachment, morphology, spreading, proliferation, and osteogenic differentiation were compared to assess in vitro osteoblastic functions on the surfaces of different materials. An in vivo test was performed on diabetic rabbits implanted with CS/PK or PK implants into the cranial bone defect to assess the osteointegration ability of the implants. In vitro results showed that diabetes inhibited osteoblastic functions evidenced by impaired morphology and spreading, and decreased attachment, proliferation, and osteogenic differentiation compared with the findings under normal conditions. Notably, CS/PK ameliorated osteoblastic disfunction under diabetic conditions in vitro. In vivo results from micro-CT and histologic examinations revealed that rabbits with CS/PK implants exhibited improved osteointegration at the bone/implant interface under diabetic conditions compared with PK. Therefore, the CS/PK composite improved the impaired osteointegration induced by diabetes and is a promising orthopedic or craniofacial implant material that may obtain good clinical performance in diabetic patients.
Subject(s)
Benzophenones/chemistry , Calcium Compounds/chemistry , Diabetes Mellitus, Experimental/drug therapy , Osseointegration/drug effects , Polymers/chemistry , Silicates/chemistry , 3T3 Cells , Animals , Biocompatible Materials/chemistry , Bone-Implant Interface , Cell Adhesion , Cell Differentiation , Cell Proliferation , Ethylene Oxide/chemistry , Female , In Vitro Techniques , Mice , Nanoparticles/chemistry , Osteoblasts/drug effects , Osteoblasts/metabolism , Osteogenesis/drug effects , Prostheses and Implants , Rabbits , Titanium/chemistry , X-Ray MicrotomographyABSTRACT
Renal ischemia-reperfusion injury is a leading cause of acute kidney injury, but its underlying mechanism remains poorly understood and effective therapies are still lacking. Here, we identified lncRNA XLOC_032768 as a novel target in renal ischemia-reperfusion injury by analyzing differentially expressed genes of the transcriptome data. PCR results show that XLOC_032768 was markedly downregulated in the kidney during renal ischemia-reperfusion in mice and in cultured kidney cells during hypoxia. Upon induction in vitro, XLOC_032768 overexpression repressed the expression of fibronectin type III domain containing 3B (FNDC3B) and tubular epithelial cells apoptosis. Administration of XLOC_032768 preserved FNDC3B expression and attenuated renal tubular epithelial cells apoptosis, resulting in protection against kidney injury in mice. Knockdown of FNDC3B markedly reduced the expression of TGF-ß1 and apoptosis of renal tubular cells. Thus, XLOC_032768/FNDC3B/TGF-ß1signaling pathway in ischemia-reperfusion injury may be targeted for therapy.
Subject(s)
Acute Kidney Injury/genetics , Fibronectins/metabolism , RNA, Long Noncoding/metabolism , Reperfusion Injury/genetics , Transforming Growth Factor beta1/metabolism , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Animals , Apoptosis/genetics , Cell Line , Epithelial Cells/metabolism , Epithelial Cells/pathology , Fibronectins/genetics , Humans , Male , Mice , Mice, Inbred C57BL , Protective Agents/pharmacology , RNA, Long Noncoding/genetics , Reperfusion Injury/complications , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Signal Transduction , Transforming Growth Factor beta1/geneticsABSTRACT
The present research focuses on the influence of CCCTC-binding factor (CTCF) on prostate cancer (PC) via the regulation of the FoxO signalling pathway. A bioinformatics analysis was conducted to screen out target genes for CTCF in LNCaP cells and to enrich the relevant pathways in LNCaP cells. It was found that the FoxO pathway was enriched according to the ChIP-seq results of CTCF. The expression of CTCF, pFoxO1a, FoxO1a, pFoxO3a and FoxO3a was tested by RT-qPCR and Western blot. Inhibition of CTCF could lead to the up-regulation of the FoxO signalling pathway. The rates of cell proliferation, cell invasion and apoptosis were examined by MTT assay, cell invasion assay and flow cytometry under different interference conditions. Down-regulation of CTCF could suppress cell proliferation, cell invasion and facilitate cell apoptosis. Lastly, the effect of CTCF on tumour growth was determined in nude mice. Inhibition of CTCF regulated the FoxO signalling pathway, which retarded tumour growth in vivo. In conclusion, CTCF regulates the FoxO signalling pathway to affect the progress of PC.
Subject(s)
CCCTC-Binding Factor/genetics , Forkhead Box Protein O1/genetics , Forkhead Box Protein O3/genetics , Prostatic Neoplasms/genetics , Animals , Apoptosis/genetics , CCCTC-Binding Factor/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/genetics , Disease Progression , Gene Expression Regulation, Neoplastic/genetics , Heterografts , Humans , Male , Mice , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/pathology , Prostatic Neoplasms/pathology , Signal Transduction/genetics , Transcriptional Activation/geneticsABSTRACT
Despite the advance of diagnosis and treatment for prostate cancer, the prognosis of metastatic prostate cancer is poor. We aimed to explore the functional role of long non-coding RNA cardiac hypertrophy-related factor (lncRNA CHRF) in prostate cancer cells (PC3) as well as the molecular mechanisms. LncRNA CHRF silence repressed cell number (%), down-regulated expression of cyclinD1, CDK4 and CDK6, and promoted apoptosis along with activation of the casapse-3 and caspase-9. LncRNA CHRF promoted mesenchymal transition (EMT), showing down-regulation of E-cadherin and up-regulation of N-cadherin, vimentin and ZEB1. Afterwards, we found miR-10b expression was positively correlated with lncRNA CHRF expression, and miR-10b inhibition could reverse the effects of lncRNA CHRF on PC3 and LNCaP cell proliferation and EMT. Finally, lncRNA CHRF was found to activate the GSK3ß/AKT and NF-κB pathways via up-regulation of miR-10b. LncRNA CHRF silence repressed proliferation and EMT while promoted apoptosis in PC3 cells via positive regulation of miR-10b. The GSK3ß/AKT and NF-κB pathways were activated by lncRNA CHRF, possibly through up-regulation of miR-10b.
ABSTRACT
PURPOSE: We performed a meta-analysis to confirm the efficacy and safety of continuous saline bladder irrigation compared with intravesical chemotherapy after transurethral resection for the treatment of non-muscle invasive bladder cancer. METHODS: Randomized controlled trials of continuous saline bladder irrigation compared with intravesical chemotherapy were searched using MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. The data were evaluated and statistically analyzed using RevMan version 5.3.0. RESULTS: Four studies including 861 participants which compared continuous saline bladder irrigation with intravesical chemotherapy were considered. One-year recurrence-free survival [odds ratio (OR) = 0.76, 95% CI = 0.55-1.05, p = 0.09]; 2-year recurrence-free survival (OR = 0.94, 95% CI = 0.71-1.25, p = 0.68); the median period to first recurrence (OR = - 1.01, 95% CI = - 2.96 to 0.94, p = 0.31); the number of tumor progression (OR = 0.80, 95% CI = 0.54-1.17, p = 0.25); and the number of recurrence during follow-up (OR = 1.12, 95% CI = 0.84-1.50, p = 0.43) suggested that two methods of postoperative perfusion had no significant differences. In terms of safety, including macrohematuria, frequency of urination and bladder irritation symptoms, continuous saline bladder irrigation showed better tolerance than intravesical chemotherapy. CONCLUSION: Continuous saline bladder irrigation seems to provide a better balance between prevention of recurrence and local toxicities than intravesical chemotherapy after transurethral resection of bladder tumors.
Subject(s)
Saline Solution/administration & dosage , Urinary Bladder Neoplasms/therapy , Administration, Intravesical , Antineoplastic Agents/administration & dosage , Combined Modality Therapy , Cystectomy/methods , Humans , Randomized Controlled Trials as Topic , Saline Solution/adverse effects , Therapeutic Irrigation/adverse effects , Therapeutic Irrigation/methods , Treatment Outcome , Urethra , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/surgeryABSTRACT
AIM: We conducted a meta-analysis to evaluate the safety and efficacy of mirabegron (50 mg) and solifenacin (5 mg) monotherapy for overactive bladder (OAB) during a 12-week cycle. METHODS: Randomized controlled trials (RCTs) of mirabegron and solifenacin for OAB were searched systematically by using MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. The reference lists of retrieved studies were also perused. RESULTS: Five RCTs which compared solifenacin with mirabegron were studied. Mirabegron achieved the same effect as solifenacin in treating OAB. The mean number of incontinence episodes per 24 h (P = 0.20), mean number of micturitions per 24 h (P = 0.11), mean number of urgency episodes per 24 h (P = 0.23), and mean volume voided per micturition (P = 0.05) suggested that mirabegron and solifenacin had no significant differences in terms of OAB treatment. With regard to drug-related treatment-emergent adverse events (DR-TEAEs) and dry mouth, mirabegron showed better tolerance than solifenacin. Post-voiding residual volume showed a distinct difference in the two groups. Hypertension and tachycardia did not show a significant difference between the two groups, but the pulse rate did. CONCLUSION: The therapeutic effect of mirabegron is similar to that of solifenacin, and mirabegron does not increase the risk of adverse events (AEs).