ABSTRACT
INTRODUCTION: A growing number of randomized controlled trials (RCTs) have demonstrated the effectiveness of tumor necrosis factor-α (TNF-α) inhibitors in treating non-radiographic axial spondyloarthritis (nr-axSpA). This study aimed to evaluate the efficacy of TNF-α inhibitors in the treatment of nr-axSpA. METHODS: PubMed, EMBASE, Web of Science, and the Cochrane Library databases were systematically searched for relevant RCTs using specific keywords up to June 2023. The primary outcome was the proportion of patients who achieved Assessment in SpondyloArthritis international Society 40% (ASAS40). Secondary outcomes included ASAS20, Bath Ankylosing Spondylitis Disease Activity Index 50% (BASDAI50), ASAS partial remission, and ASAS5/6. RESULTS: A total of eight RCTs involving 1,376 patients were included. Patients receiving anti-TNF therapy exhibited a higher rate of ASAS40 (pooled RR = 2.36; 95% CI: 1.63-3.42; p < 0.001). In addition, the TNF-α inhibitor group showed higher BASDAI50 rates (pooled RR = 2.06; 95% CI: 1.48-2.89), ASAS20 rates (pooled RR = 1.48; 95% CI: 1.31-1.67), ASAS partial remission rates (pooled RR = 2.33; 95% CI: 1.58-3.43), and ASAS5/6 rates (RR = 3.46; 95% CI: 2.05-5.83) than the placebo group. CONCLUSION: The TNF-α inhibitors were effective in treating nr-axSpA.
Subject(s)
Randomized Controlled Trials as Topic , Tumor Necrosis Factor-alpha , Humans , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Treatment Outcome , Spondylarthritis/drug therapy , Antirheumatic Agents/therapeutic use , Spondylitis, Ankylosing/drug therapyABSTRACT
The purpose of this study is to further investigate the relationship between sweetener exposure and the risk of endometrial cancer (EC). Up until December 2022, a literature search in an electronic database was carried out utilizing PubMed, Web of Science, Ovid, and Scopus. The odds ratio (OR) and 95 % confidence interval (CI) were used to evaluate the results. Sweeteners were divided into nutritional sweeteners (generally refers to sugar, such as sucrose and glucose) and non-nutritional sweeteners (generally refers to artificial sweeteners, such saccharin and aspartame). Ten cohort studies and two case-control studies were eventually included. The study found that in 12 studies, compared with the non-exposed group, the incidence rate of EC in the sweetener exposed group was higher (OR = 1·15, 95 % CI = [1·07, 1·24]). Subgroup analysis showed that in 11 studies, the incidence rate of EC in the nutritional sweetener exposed group was higher than that in the non-exposed group (OR = 1·25, 95 % CI = [1·14, 1·38]). In 4 studies, there was no difference in the incidence rate of EC between individuals exposed to non-nutritional sweeteners and those who were not exposed to non-nutritional sweeteners (OR = 0·90, 95 % CI = [0·81, 1·01]). This study reported that the consumption of nutritional sweeteners may increase the risk of EC, whereas there was no significant relationship between the exposure of non-nutritional sweeteners and the incidence of EC. Based on the results of this study, it is recommended to reduce the intake of nutritional sweeteners, but it is uncertain whether use of on-nutritional sweeteners instead of nutritional sweetener.
Subject(s)
Endometrial Neoplasms , Non-Nutritive Sweeteners , Female , Humans , Aspartame/adverse effects , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/etiology , Non-Nutritive Sweeteners/adverse effects , Saccharin/adverse effects , Sucrose/adverse effects , Sweetening Agents/adverse effects , Observational Studies as TopicABSTRACT
PURPOSE: This study was conducted to investigate the relationship between cesarean section (CS) offspring and autism spectrum disorders (ASD)/attention deficit hyperactivity disorder (ADHD). METHODS: Searching of the databases (PubMed, Web of Science, Embase, and Cochrane Library) for studies on the relationship between mode of delivery and ASD/ADHD until August 2022. The primary outcome was the incidence of ASD/ADHD in the offspring. RESULTS: This meta-analysis included 35 studies (12 cohort studies and 23 case-control studies). Statistical results showed a higher risk of ASD (odds ratio (OR) = 1.25, P < 0.001) and ADHD (OR = 1.11, P < 0.001) in CS offspring compared to the VD group. Partial subgroup analysis showed no difference in ASD risk between CS and VD offspring in sibling-matched groups (OR = 0.98, P = 0.625). The risk of ASD was higher in females (OR = 1.66, P = 0.003) than in males (OR = 1.17, P = 0.004) in the CS offspring compared with the VD group. There was no difference in the risk of ASD between CS under regional anesthesia group and VD group (OR = 1.07, P = 0.173). However, the risk of ASD was higher in the CS offspring under general anesthesia than in the VD offspring (OR = 1.62, P < 0.001). CS offspring developed autism (OR = 1.38, P = 0.011) and pervasive developmental disorder-not otherwise specified (OR = 1.46, P = 0.004) had a higher risk than VD offspring, but there was no difference in Asperger syndrome (OR = 1.19, P = 0.115). Offspring born via CS had a higher incidence of ADHD in different subgroup analyses (sibling-matched, type of CS, and study design). CONCLUSIONS: In this meta-analysis, CS was a risk factor for ASD/ADHD in offspring compared with VD.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Autism Spectrum Disorder , Male , Humans , Female , Pregnancy , Cesarean Section/adverse effects , Autism Spectrum Disorder/etiology , Autism Spectrum Disorder/complications , Attention Deficit Disorder with Hyperactivity/epidemiology , Attention Deficit Disorder with Hyperactivity/etiology , Siblings , Risk FactorsABSTRACT
Exploring the roles of long noncoding RNAs (lncRNAs) in tumorigenesis and metastasis could contribute to the recognition of novel diagnostic and therapeutic targets. LINC02870 is a novel lncRNA, whose role in tumors has not been reported. Herein, we focused on the function and mechanism of LINC02870 in human hepatocellular carcinoma (HCC). We first carried out a pan-cancer study of LINC02870 expression and its relationship to prognosis, and LINC02870 was determined to be a possible oncogene in HCC. Upregulated expressions of LINC02870 were also found in our HCC samples compared to the para-tumor samples. Moreover, overexpression of LINC02870 promoted the growth, migration, and invasion of HCC cells. Subsequently, binding proteins of LINC02870 were identified by a number of in silico analyses, including correlation analysis, signaling network analysis, and survival analysis. Intriguingly, the most promising binding protein of LINC02870 was predicted and confirmed to be eukaryotic translation initiation factor 4 gamma 1 (EIF4G1), an important component of the eukaryotic translation initiation factor 4F complex that initiates cap-dependent translation. Further investigation showed that LINC02870 increased the translation of SNAIL to induce malignant phenotypes in HCC cells. Additionally, HCC patients with higher expression levels of LINC02870 and EIF4G1 had shorter survival times than those with lower expression levels. Thus, our findings suggested that LINC02870 induced SNAIL translation and correlated with poor prognosis and tumor progression in HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , MicroRNAs , RNA, Long Noncoding , Humans , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Signal Transduction , Cell Transformation, Neoplastic/genetics , Carcinogenesis/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Gene Expression Regulation, Neoplastic , Cell Proliferation , Cell Line, Tumor , MicroRNAs/genetics , Cell MovementABSTRACT
This study intends to conduct a meta-analysis based on existing research results to further investigate their relationship between artificial sweetener exposure and breast cancer risk. An electronic database literature search was performed up to July 2022, using PubMed, Web of Science, Ovid and Scopus. The relationship between artificial sweetener exposure and breast cancer (BC) incidence was evaluated by odds ratio (OR) and 95% confidence interval (CI). Among the five studies (two case-control studies and three cohort studies) that met the inclusion criteria, 314,056 participants were recruited in the cohort study, 4,043 cancer cases and 3,910 controls were recruited in the case-control study. It was found that exposure of artificial sweeteners was not related to the risk of BC (OR = 0.98, 95% CI = [0.94-1.03]). Subgroup analysis showed that compared with the non-exposure/very-low-dose group, the exposure to low, medium and high doses of artificial sweeteners were not associated with the risk of BC, which were OR = 1.01, 95% CI = [0.95-1.07], OR = 0.98, 95% CI = [0.93-1.02], OR = 0.88, 95% CI = [0.74-1.06], respectively. This study confirmed that there was no relationship between the exposure of artificial sweeteners and the incidence of BC.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/chemically induced , Breast Neoplasms/epidemiology , Sweetening Agents/adverse effects , Cohort Studies , Case-Control StudiesABSTRACT
BACKGROUND: Whether cesarean section (CS) is a risk factor for asthma in offspring is controversial. The purpose of this study was to investigate the association between CS and asthma in children/adolescents. METHODS: Pubmed, Embase, Web of Science, and Cochrane Library electronic databases were searched for cohort studies on the relationship between mode of delivery and asthma in children/adolescents up to February 2023. Birth via CS was considered an exposure factor. Asthma incidence was taken as a result. RESULTS: Thirty-five cohort studies (thirteen prospective and twenty-two retrospective cohort studies) were included. The results showed that the incidence of asthma was higher in CS offspring (odds ratio (OR) = 1.18, P < 0.001) than in the vaginal delivery (VD) group. Partial subgroup analyses showed a higher incidence of asthma in female offspring born via CS (OR = 1.26, P < 0.001) compared with the VD group, while there was no difference in males (OR = 1.07, P = 0.325). Asthma incidence was higher in CS offspring than in the VD group in Europe (OR = 1.20, P < 0.001), North America (OR = 1.15, P < 0.001), and Oceania (OR = 1.06, P = 0.008). This trend was not found in the Asian population (OR = 1.17, P = 0.102). The incidence of atopic asthma was higher in offspring born via CS (OR = 1.14, P < 0.001) compared to the VD group. The CS group had a higher incidence of persistent asthma, but the difference did not reach statistical significance (OR = 1.15, P = 0.063). CONCLUSION: In this meta-analysis, CS may be a risk factor for asthma in offspring children/adolescents compared with VD. The relationship between CS and asthma was influenced by sex and region.
Subject(s)
Asthma , Cesarean Section , Male , Child , Female , Adolescent , Humans , Pregnancy , Cesarean Section/adverse effects , Retrospective Studies , Prospective Studies , Cohort Studies , Asthma/epidemiology , Asthma/etiologyABSTRACT
Structure-activity relationships have been developed around 5-bromo-8-toluylsulfonamidoquinoline 1 a hit compound in an assay for the interaction of the E3 ligase Skp2 with Cks1, part of the SCF ligase complex. Disruption of this protein-protein interaction results in higher levels of CDK inhibitor p27, which can act as a tumor suppressor. The results of the SAR developed highlight the relationship between the sulfonamide and quinoline nitrogen, while also suggesting that an aryl substituent at the 5-position of the quinoline ring contributes to the potency in the interaction assay. Compounds showing potency in the interaction assay result in greater levels of p27 and have been shown to inhibit cell growth of two p27 sensitive tumor cell lines.
Subject(s)
Aminoquinolines/pharmacology , Antineoplastic Agents/pharmacology , CDC2-CDC28 Kinases/antagonists & inhibitors , S-Phase Kinase-Associated Proteins/antagonists & inhibitors , Sulfonamides/pharmacology , Aminoquinolines/chemical synthesis , Antineoplastic Agents/chemical synthesis , CDC2-CDC28 Kinases/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Drug Screening Assays, Antitumor , Humans , S-Phase Kinase-Associated Proteins/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
Coordination of filament assembly and membrane remodeling is required for the directional migration of cancer cells. The Wiskott-Aldrich syndrome protein (WASP) recruits the actin-related protein (ARP) 2/3 complex to assemble branched actin networks. The goal of our study was to assess the potential regulatory role exerted by the novel long noncoding RNA (lncRNA) LINC00869 on hepatocellular carcinoma (HCC) cells. We used HCC cells to overexpress or knockdown LINC00869, analyzed patient data from publicly available databases and Cancer Hospital Affiliated with Zhengzhou University, and used a xenograft mouse model of HCC to study the molecular mechanism associated with LINC00869 expression. We found that high levels of LINC00869 expression were associated with poor prognosis in patients with HCC. Next, we detected an interaction between LINC00869 and both WASP and ARP2 in HCC cells, and observed a modulatory effect of LINC00869 on the phosphorylation of WASP at Y291 and the activity of cell division control protein 42 (CDC42). These modulatory roles were required for WASP/CDC42 activity on F-actin polymerization to enhance membrane protrusion formation and maintain persistent cell polarization. This, in turn, promoted the migration and invasion abilities of HCC cells. Finally, we confirmed the role of LINC00869in vivo, using the tumor xenograft mouse model; and identified a positive correlation between LINC00869 expression levels and the phosphorylation levels of WASP in HCC samples. Overall, our findings suggest a unique mechanism by which LINC00869 orchestrates membrane protrusion during migration and invasion of HCC cells. IMPLICATIONS: LncRNA LINC00869 regulates the activity of CDC42-WASP pathway and positively affects protrusion formation in HCC cells, which expands the current understanding of lncRNA functions as well as gives a better understanding of carcinogenesis.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , RNA, Long Noncoding , Humans , Animals , Mice , Carcinoma, Hepatocellular/genetics , Actins , RNA, Long Noncoding/genetics , Liver Neoplasms/genetics , Phosphorylation , Actin-Related Protein 2-3 Complex/genetics , Disease Models, AnimalABSTRACT
Background: Metformin is one of the most common drugs for type 2 diabetes mellitus (T2DM) treatment. In addition, metformin intends to have a positive effect on the prognosis of several cancers. However, the therapeutic effect of metformin on gastric cancer (GC) remains controversial. This study explores and updates the therapeutic effect of metformin in GC patients with T2DM. Methods: We searched through PubMed, Embase, Web of Science, and the Cochrane Library for relevant articles by July 2022. The relationship between metformin therapy and the prognosis of GC patients with T2DM was evaluated based on the hazard ratio (HR) at a 95% confidence interval (95% CI). Overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) were the primary outcomes analyzed. Results: Seven retrospective cohort studies with a combined 2,858 patients met the inclusion criteria. OS and CSS were reported in six studies, and PFS was reported in four studies. Pooled results showed that, compared to the nonmetformin group, the prolonged OS (HR = 0.72, p = 0.001), CSS (HR = 0.81, p = 0.001), and PFS (HR = 0.70, p = 0.008) of the experimental group may be associated with the exposure to metformin. Conclusion: Metformin may have a beneficial effect on the prognosis of GC patients with T2DM.
ABSTRACT
BACKGROUND: The health-related quality of life (HRQoL) of patients with localized prostate cancer (LPCa) after treatment mainly surgery and radiotherapy (RT) has received increasing attention. The aim of this study is to compare the HRQoL of LPCa after surgery and RT. METHODS: Web of Science, Embase, PubMed and Cochrane databases were searched after January 2000 to observe the HRQoL scores after surgery and RT at different treatment time points. RESULTS: A total of 28 studies were included in this study, and the results showed that LPCa received surgery had better bowel scores than RT at ≤3 (weighted mean differences [WMD] = 4.18; p = 0.03), 3-6 (WMD = 4.16; p < 0.001), 6-12 (WMD = 2.99; p = 0.004), 24-60 (WMD = 1.87; p = 0.06), and ≥60 (WMD = 4.54; p = 0.02) months. However, LPCa received RT had higher urinary scores at ≤3 (WMD = -7.39; p = 0.02), 3-6 (WMD = -6.03; p = 0.02), 6-12 (WMD = -4.90; p < 0.001), 24-60 (WMD = -3.96; p < 0.001), ≥60 (WMD = -2.95; p < 0.001) months and had better sexual scores at ≤3 (WMD = -13.58; p = 0.09), 3-6 (WMD = -12.32; p = 0.06), 6-12 (WMD = -12.03; p = 0.002), 24-60 (WMD = -11.29; p < 0.001), and ≥60 (WMD = -3.10; p = 0.46) months than surgery. The scores difference between surgery and RT decreased over time. CONCLUSION: Overall, for LPCa, surgery was associated with better HRQoL in the bowel domain, whereas RT was associated with better HRQoL in the urinary and sexual domains, with the difference between surgery and RT narrowing over time.
ABSTRACT
It is widely thought that statins have huge therapeutic potential against prostate cancer (PCA). This study aimed to investigate the effect of statin exposure on PCA incidence and prognosis. PubMed, Web of Science, Embase, and Cochrane databases were searched for observational studies on the association between statin exposure and PCA from inception until July 2022. The primary endpoints were the incidence of PCA and the survival rate. A total of 21 studies were included in this meta-analysis. The pooled estimates showed that exposure to hydrophilic statins was not associated with the incidence of PCA (odds ratio [OR]=0.94, 95% CI=0.88-1.01, P =0.075), while the incidence of PCA was significantly decreased in populations exposed to lipophilic statins compared with the nonexposed group (OR=0.94, 95% CI=0.90-0.98, P =0.001), mainly in Western countries (OR=0.94, 95% CI=0.91-0.98, P =0.006). Subgroup analysis showed that simvastatin (OR=0.83, 95% CI=0.71-0.97, P =0.016) effectively reduced the incidence of PCA. The prognosis of PCA in patients exposed to both hydrophilic (hazard ratio [HR]=0.57, 95% CI=0.49-0.66, P <0.001) and lipophilic (HR=0.65, 95% CI=0.58-0.73, P <0.001) statins were better than in the nonexposed group, and this improvement was more significant in the East than in Western countries. This study demonstrates that statins can reduce the incidence of PCA and improve prognosis, and are affected by population region and statin properties (hydrophilic and lipophilic).
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Prostatic Neoplasms , Male , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Incidence , Prognosis , Simvastatin , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/drug therapyABSTRACT
T cell-stimulating cytokines and immune checkpoint inhibitors (ICI) are an ideal combination for increasing response rates of cancer immunotherapy. However, the results of clinical trials have not been satisfying. It is important to understand the mechanism of synergy between these two therapeutic modalities. Here, through integrated analysis of multiple single-cell RNA sequencing (scRNA-seq) datasets of human tumor-infiltrating immune cells, we demonstrate that IL21 is produced by tumor-associated T follicular helper cells and hyperactivated/exhausted CXCL13+CD4+ T cells in the human tumor microenvironment (TME). In the mouse model, the hyperactivated/exhausted CD4+ T cell-derived IL21 enhances the helper function of CD4+ T cells that boost CD8+ T cell-mediated immune responses during PD-1 blockade immunotherapy. In addition, we demonstrated that IL21's antitumor activity did not require T-cell trafficking. Using scRNA-seq analysis of the whole tumor-infiltrating immune cells, we demonstrated that IL21 treatment in combination with anti-PD-1 blockade synergistically drives tumor antigen-specific CD8+ T cells to undergo clonal expansion and differentiate toward the hyperactive/exhausted functional state in the TME. In addition, IL21 treatment and anti-PD-1 blockade synergistically promote dendritic cell (DC) activation and maturation to mature DC as well as monocyte to type 1 macrophage (M1) differentiation in the TME. Furthermore, the combined treatment reprograms the immune cellular network by reshaping cell-cell communication in the TME. Our study establishes unique mechanisms of synergy between IL21 and PD-1-based ICI in the TME through the coordinated promotion of type 1 immune responses. Significance: This study reveals how cytokine and checkpoint inhibitor therapy can be combined to increase the efficacy of cancer immunotherapy.
Subject(s)
CD8-Positive T-Lymphocytes , Tumor Microenvironment , Animals , Mice , Humans , Interleukins/pharmacology , Immunotherapy/methods , CytokinesABSTRACT
This paper investigates the regularity of microstructural evolution of Shenzhen granite residual soil in an attempt to determine its macrostructural deformation characteristics. The pore distribution and microstructure characteristics of granite residual soil are examined experimentally under different consolidation stresses, coupled with mercury injection tests and scanning electron microscopy. It is found that a microstructure exists in the granite residual soil and that the structural characteristics of granite residual soil in Shenzhen. The calculated pre-consolidation stress and structural yield strength of the granite residual soil are similar, indicating a phenomenon that resembles over-consolidation in the granite residual soil. This is fundamentally different from the mechanism of conventional over-consolidation in soil. It is also found that the relationship between the increment of mercury in soil samples and the stress of the mercury under different consolidation stresses is mainly trimodal. The significance of the research presented in this paper lies in the development of a clear understanding of the influence of the microstructure characteristics of granite residual soil on its macrostructural deformation, thereby providing a theoretical basis for engineering applications involving granite residual soil and the analysis of foundation deformation.
ABSTRACT
Sensitive and visual analysis of iodide (I-) and pH is significant in environmental and food applications. Herein, we present a facile fluorescent sensor for highly selective and visual detection of I- and pH based on nitrogen-doped carbon dots derived from Listeria monocytogenes (NCDs-LM). The NCDs-LM-based fluorescent sensor showed a good linear relationship to I- concentrations, and the detection limit was calculated as 20 nmol L-1. The developed sensor was successfully applied to the detection of I- in drinking water and milk samples. Meanwhile, the as-synthesized NCDs-LM sensor can be used to detect pH, achieving a wide linear pH range. Furthermore, fluorescent test papers based on NCDs-LM were designed for semi-quantitative detection of I- and pH via the naked-eye colorimetric assay. The present work indicates that the NCDs-LM-based fluorescent sensor has high potential for use in environmental monitoring and food analysis.
ABSTRACT
An unexpected discovery of new trans-4-acetyl-1,9-dimethyl-4,4a-dihydro-3H-fluoren-3-ones from one pot reactions of benzaldehydes and acetylacetone is described. The synthetic mechanism and stereochemistry were discussed. These new derivatives exhibit good fluorescent properties in solutions.
Subject(s)
Aldehydes/chemistry , Chemistry, Organic/methods , Fluorenes/chemistry , Fluorenes/chemical synthesis , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Cell Line, Tumor , Crystallography, X-Ray , Fluorescence , Humans , Microscopy, Confocal , Spectrometry, Fluorescence , Spectrophotometry, Ultraviolet , StereoisomerismABSTRACT
Both entecavir and crizotinib are substrates of organic cation transporter 2 (OCT2). The aim of present study was to investigate the mechanisms of drug interactions between these two drugs. Kinetic analysis of entecavir on crizotinib uptake was conduct. Plasma concentration of crizotinib in rats and lung cancer patients, uptake of crizotinib in kidney slices and OCT2 transfected cells, were determined by LC-MS/MS. The clinical pharmacokinetic interactions and impact on adverse reaction of crizotinib in lung cancer patients were investigated. Steady-state through concentration of crizotinib was measured. The crizotinib-related adverse reactions were recorded in lung cancer patients with and without entecavir. Entecavir and 1-methyl-4-phenylpyridinium iodide significantly inhibited the uptake of crizotinib in kidney slices. Kinetic constants for crizotinib uptake by OCT2 were Km 1.16 ± 0.26 µM, Vmax 12.05 ± 0.53 µmol/min mg-1 protein and Ki 9.711 nM. Entecavir can inhibit crizotinib transport by OCT2 in kidney. Co-administration of entecavir significantly reduced the elimination of crizotinib in rats. In lung cancer patients, the steady-state AUCss of crizotinib increased approximately 1.2 fold (p < 0.05) but clearance was decreased by approximately 15% in the presence of entecavir. Steady-state through concentration of crizotinib significantly increased 1.3-fold when co-administrated with entecavir (p>0.001). Co-medication of entecavir significantly (p < 0.05) increased the risks of vision disorders, diarrhea and vomiting 1.6-, 2.3- and 1.8-fold. Entecavir could increase the exposure and reduce the elimination of crizotinib in lung cancer patients. Moreover, the presence of entecavir could significantly increase the incidences of adverse reaction of crizotinib.
Subject(s)
Crizotinib/metabolism , Drug Interactions/physiology , Guanine/analogs & derivatives , Kidney/metabolism , Organic Cation Transporter 2/metabolism , Animals , Biological Transport/physiology , Guanine/metabolism , HEK293 Cells , Humans , Kinetics , Lung Neoplasms/metabolism , Male , Rats , Rats, Sprague-DawleyABSTRACT
Small-molecule library screening to find compounds that inhibit TNFalpha-induced, but not interleukin 1beta (IL-1beta)-induced, intercellular adhesion molecule 1 (ICAM-1) expression in lung epithelial cells identified a class of triazoloquinoxalines. These compounds not only inhibited the TNFalpha-induced nuclear factor kappaB (NFkappaB) survival pathway but also blocked death-pathway activation. Such dual activity makes them unique against other known NFkappaB-pathway inhibitors that inhibit only a subset of TNFalpha signals leading to increased TNFalpha-induced cytotoxicity. Interestingly, these compounds inhibited association of TNFalpha receptor (TNFalphaR) I with TNFalphaR-associated death domain protein (TRADD) and receptor interacting protein 1 (RIP1), the initial intracellular signaling event following TNFalpha stimulation. Further study showed that they blocked ligand-dependent internalization of the TNFalpha-TNFalphaR complex, thereby inhibiting most of the TNFalpha-induced cellular responses. Thus, compounds with a triazoloquinoxaline scaffold could be a valuable tool to investigate small molecule-based anti-TNFalpha therapies.
Subject(s)
Apoptosis/drug effects , Enzyme Inhibitors/pharmacology , Intercellular Adhesion Molecule-1/metabolism , Quinoxalines/pharmacology , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Receptors, Tumor Necrosis Factor, Type I/metabolism , TNF Receptor-Associated Death Domain Protein/metabolism , Triazoles/pharmacology , Tumor Necrosis Factor-alpha , Apoptosis/physiology , Cell Membrane/chemistry , Cell Membrane/metabolism , Epithelial Cells/cytology , Epithelial Cells/pathology , Gene Expression Regulation/genetics , Gene Expression Regulation/physiology , Intercellular Adhesion Molecule-1/genetics , Lung/cytology , Lung/pathology , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Receptors, Tumor Necrosis Factor, Type I/genetics , Signal Transduction/genetics , Signal Transduction/physiology , Small Molecule Libraries , TNF Receptor-Associated Death Domain Protein/geneticsABSTRACT
Early cellular events associated with tumorigenesis often include loss of cell cycle checkpoints or alteration in growth signaling pathways. Identification of novel genes involved in cellular proliferation may lead to new classes of cancer therapeutics. By screening a tetracycline-inducible cDNA library in A549 cells for genes that interfere with proliferation, we have identified a fragment of UHRF1 (ubiquitin-like protein containing PHD and RING domains 1), a nuclear RING finger protein, that acts as a dominant negative effector of cell growth. Reduction of UHRF1 levels using an UHRF1-specific shRNA decreased growth rates in several tumor cell lines. In addition, treatment of A549 cells with agents that activated different cell cycle checkpoints resulted in down-regulation of UHRF1. The primary sequence of UHRF1 contains a PHD and a RING motif, both of which are structural hallmarks of ubiquitin E3 ligases. We have confirmed using an in vitro autoubiquitination assay that UHRF1 displays RING-dependent E3 ligase activity. Overexpression of a GFP-fused UHRF1 RING mutant that lacks ligase activity sensitizes cells to treatment with various chemotherapeutics. Taken together, our results suggest a general requirement for UHRF1 in tumor cell proliferation and implicate the RING domain of UHRF1 as a functional determinant of growth regulation.
Subject(s)
CCAAT-Enhancer-Binding Proteins/metabolism , Cell Division/physiology , Neoplasms/enzymology , Binding Sites , CCAAT-Enhancer-Binding Proteins/chemistry , CCAAT-Enhancer-Binding Proteins/genetics , Cell Line, Tumor , Cloning, Molecular , HeLa Cells , Humans , Kinetics , Oligonucleotides, Antisense , Recombinant Proteins/metabolism , Retroviridae/genetics , Transcription, Genetic , Ubiquitin-Protein LigasesABSTRACT
One new alkaloid, named as acremolin C (1), was isolated from static culture of Antarctic fungus, Aspergillus sydowii SP-1, in an investigation of the antimicrobial constituents of this Antarctic microorganism, and its structure was determined by spectroscopic methods. Additionally, four known compounds, cyclo-(L-Trp-L-Phe) (2), 4-hydroxyphenylacetic acid (3), (7S)-(+)-hydroxysydonic acid (4) and (7S, 11S)-(+)-12-hydroxysydonic acid (5), were isolated and identified. Biological studies disclosed that compounds 2, 4 and 5 showed moderate inhibitions against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) as comparing to tigecycline, while compound 1 displayed weak inhibition activities against MRSA and MRSE.
Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Aspergillus/chemistry , Antarctic Regions , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Molecular Structure , Phenylacetates/analysis , Phenylacetates/pharmacology , Sesquiterpenes/analysis , Sesquiterpenes/pharmacology , Staphylococcus epidermidis/drug effectsABSTRACT
PURPOSE: The design and development of synthetic small molecules to disrupt microtubule dynamics is an attractive therapeutic strategy for anticancer drug discovery research. Loss of clinical efficacy of many useful drugs due to drug resistance in tumor cells seems to be a major hurdle in this endeavor. Thus, a search for new chemical entities that bind tubulin, but neither are a substrate of efflux pump, P-glycoprotein 170/MDR1, nor cause undesired side effects, would potentially increase the therapeutic index in certain cancer treatments. EXPERIMENTAL DESIGN: A high-content cell-based screen of a compound library led to the identification of a new class of compounds belonging to a thienopyrimidine series, which exhibited significant antitumor activities. On structure-activity relationship analysis, R-253 [N-cyclopropyl-2-(6-(3,5-dimethylphenyl)thieno[3,2-d]pyrimidin-4-yl)hydrazine carbothioamide] emerged as a potent antiproliferative agent (average EC(50), 20 nmol/L) when examined in a spectrum of tumor cell lines. RESULTS: R-253 is structurally unique and destabilizes microtubules both in vivo and in vitro. Standard fluorescence-activated cell sorting and Western analyses revealed that the effect of R-253 on cell growth was associated with cell cycle arrest in mitosis, increased select G(2)-M checkpoint proteins, and apoptosis. On-target activity of R-253 on microtubules was further substantiated by immunofluorescence studies and selected counter assays. R-253 competed with fluorescent-labeled colchicine for binding to tubulin, indicating that its binding site on tubulin could be similar to that of colchicine. R-253 neither is a substrate of P-glycoprotein 170/MDR1 nor is cytotoxic to nondividing human hepatocytes. CONCLUSION: Both biochemical and cellular mechanistic studies indicate that R-253 could become a promising new tubulin-binding drug candidate for treating various malignancies.