N6-methyladenosine-related lncRNAs identified as potential biomarkers for predicting the overall survival of Asian gastric cancer patients.

OBJECTIVE: Gastric cancer (GC) is one of the most prevalent malignant tumors in Asian countries. Studies have proposed that lncRNAs can be used as diagnostic and prognostic indicators of GC due to the high specificity of lncRNAs expression involvement in GC. Recently, N6-methyladenosine (m6A) has also emerged as an important modulator of the expression of lncRNAs in GC. This study aimed at establishing a novel m6A-related lncRNAs prognostic signature that can be used to construct accurate models for predicting the prognosis of GC in the Asian population. METHODS: First, the levels of m6A modification and m6A methyltransferases expression in GC samples were determined using dot blot and western blot analyses. Next, we evaluated the lncRNAs expression profiles and the corresponding clinical data of 88 Asian GC patients retrieved from The Cancer Genome Atlas (TCGA) database. Differential expression of m6A-related lncRNAs between GC and normal tissues was investigated. The relationship between these target lncRNAs and potential immunotherapeutic signatures was also analyzed. Gene set enrichment analysis (GSEA) was performed to identify the malignancy-associated pathways. Univariate Cox regression, LASSO regression, and multivariate Cox regression analyses were performed to establish a novel prognostic m6A-related lncRNAs prognostic signature. Moreover, we constructed a predictive nomogram and determined the expression levels of nine m6A-related lncRNAs in 12 pairs of clinical samples. RESULTS: We found that m6A methylation levels were significantly increased in GC tumor samples compared to adjacent normal tissues, and the increase was positively correlated with tumor stage. Patients were then divided into two clusters (cluster 1 and cluster 2) based on the differential expression of the m6A-related lncRNAs. Results showed that there was a significant difference in survival probability between the two clusters (p = 0.018). Notably, the low survival rate in cluster 2 may be associated with high expression of immune cells (resting memory CD4+ T cells, p = 0.027; regulatory T cells, p = 0.0018; monocytes, p = 0.00095; and resting dendritic cells, p = 0.015), and low expression of immune cells (resting NK cells, p = 0.033; and macrophages M1, p = 0.045). Enrichment analysis indicated that malignancy-associated biological processes were more common in the cluster 2 subgroup. Finally, the risk model comprising of six m6A-related lncRNAs was identified as an independent predictor of prognoses, which could divide patients into high- or low-risk groups. Time-dependent ROC analysis suggested that the risk score could accurately predict the prognosis of GC patients. Patients in the high-risk group had worse outcomes compared to patients in the low-risk group, and the risk score showed a positive correlation with immune cells (resting memory CD4+ T cells, R = 0.31, P = 0.038; regulatory T cells, R = 0.42, P = 0.0042; monocytes, R = 0.42, P = 0.0043). However, M1 macrophages (R = -0.37, P = 0.012) and resting NK cells (R = -0.31, P = 0.043) had a negative correlation with risk scores. Furthermore, analysis of clinical samples validated the weak positive correlation between the risk score and tumor stage. CONCLUSIONS: The risk model described here, based on the six m6A-related lncRNAs signature, and may predict the clinical prognoses and immunotherapeutic response in Asian GC patients.

Prognostic value of a novel glycolysis-related gene expression signature for gastrointestinal cancer in the Asian population.

BACKGROUND: Globally, gastrointestinal (GI) cancer is one of the most prevalent malignant tumors. However, studies have not established glycolysis-related gene signatures that can be used to construct accurate prognostic models for GI cancers in the Asian population. Herein, we aimed at establishing a novel glycolysis-related gene expression signature to predict the prognosis of GI cancers. METHODS: First, we evaluated the mRNA expression profiles and the corresponding clinical data of 296 Asian GI cancer patients in The Cancer Genome Atlas (TCGA) database (TCGA-LIHC, TCGA-STAD, TCGA-ESCA, TCGA-PAAD, TCGA-COAD, TCGA-CHOL and TCGA-READ). Differentially expressed mRNAs between GI tumors and normal tissues were investigated. Gene Set Enrichment Analysis (GSEA) was performed to identify glycolysis-related genes. Then, univariate, LASSO regression and multivariate Cox regression analyses were performed to establish a key prognostic glycolysis-related gene expression signature. The Kaplan-Meier and receiver operating characteristic (ROC) curves were used to evaluate the efficiency and accuracy of survival prediction. Finally, a risk score to predict the prognosis of GI cancers was calculated and validated using the TCGA data sets. Furthermore, this risk score was verified in two Gene Expression Omnibus (GEO) data sets (GSE116174 and GSE84433) and in 28 pairs of tissue samples. RESULTS: Prognosis-related genes (NUP85, HAX1, GNPDA1, HDLBP and GPD1) among the differentially expressed glycolysis-related genes were screened and identified. The five-gene expression signature was used to assign patients into high- and low-risk groups (p < 0.05) and it showed a satisfactory prognostic value for overall survival (OS, p = 6.383 × 10-6). The ROC curve analysis revealed that this model has a high sensitivity and specificity (0.757 at 5 years). Besides, stratification analysis showed that the prognostic value of the five-gene signature was independent of other clinical characteristics, and it could markedly discriminate between GI tumor tissues and normal tissues. Finally, the expression levels of the five prognosis-related genes in the clinical tissue samples were consistent with the results from the TCGA data sets. CONCLUSIONS: Based on the five glycolysis-related genes (NUP85, HAX1, GNPDA1, HDLBP and GPD1), and in combination with clinical characteristics, this model can independently predict the OS of GI cancers in Asian patients.

Identification of 5-hydroxymethylfurfural in cigarette smoke extract as a new substrate metabolically activated by human cytochrome P450 2A13.

Cytochrome P450 2A13 (CYP2A13) is an extrahepatic enzyme mainly expressed in the human respiratory system and is reported to mediate tobacco-specific N-nitrosamines (TSNA) metabolism in cigarette smoke. This study aimed to identify other new substrates of CYP2A13 in cigarette smoke and their corresponding respiratory toxicity. Following separation by HPLC, GC-MS/MS, NMR and cytotoxicity assays in BEAS-2B cells stably expressing CYP2A13 (B-2A13), 5-Hydroxymethylfurfural (5-HMF) was screened and identified in the 4-5 min section of cigarette smoke extract (CSE). In vitro metabolism results showed that CYP2A13 mediated the fast clearance of 5-HMF and formed the metabolite 5-HMF acid (5-HMFA). CSE 5-HMF (CSE-5-HMF) showed cytotoxicity similar to that of standard 5-HMF in B-2A13 and B-2A5 cells, which was inhibited by 8-methoxypsoralen (8-MOP), a CYP enzyme inhibitor. Mouse CYP2A5, a homologous CYP enzyme to CYP2A13, shares many substrates with CYP2A13 in cigarette smoke. Thus, CYP2A5-/- mice were generated to explore the role of CYP2A5 in 5-HMF bioactivation. Compared with CYP2A5-/- mice, WT mice showed serious histological lung and nasal olfactory mucosa damage, as well as increased inflammatory cells and elevated TNF-α and IL-6 levels in bronchoalveolar lavage fluid. Besides, nasal microsomes undertook fast 5-HMFA formation in WT mice than that in CYP2A5-/- mice, which could be inhibited by 8-MOP. This study is the first to identify 5-HMF as a new toxic substrate of human CYP2A13 in cigarette smoke, it may play a potential role in cigarette smoke-induced respiratory injuries.

CDK1 Acts as a Prognostic Biomarker Associated with Immune Infiltration in Pan-Cancer, Especially in Gastrointestinal Tumors.

OBJECTIVE: Cyclin-dependent kinase 1 (CDK1) regulates the cell cycle and is highly expressed in most tumors. CDK1 expression has been associated with poor disease prognosis. This study aimed to identify the prognostic value of CDK1 in pan-cancer and investigate the association between CDK1 expression and immune cell infiltration. METHODS: CDK1 expression and its correlation with prognosis in pan-cancer were analyzed using online databases. Immune infiltration was assessed by ESTIMATE and CIBERSORT algorithms. We then evaluated the relationship between CDK1 expression and tumor mutational burden (TMB), microsatellite instability (MSI), or tumor-infiltrating immune cells. In addition, we performed the co-expression analysis of immune-related genes and GO analysis with CDK1 expression in pan-cancer. Finally, we compared the CDK1 expression profile with the immune-related genes in 30 pairs of clinical gastrointestinal tumor samples. RESULTS: Our analysis demonstrated overexpression of CDK1 in most tumor tissues, especially in gastrointestinal tumors. The high expression of CDK1 was associated with poor overall survival, disease-specific survival, disease-free interval, and progression-free interval in kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), and sarcoma (SARC). Besides, CDK1 expression was significantly associated with TMB in 22 cancer types and MSI in 8 cancer types as well as greater frequencies of MSI-high (MSI-H) status and high tumor mutational burden (TMB-H) in uterine corpus endometrial carcinoma (UCEC), stomach adenocarcinoma (STAD), sarcoma (SARC), rectum adenocarcinoma (READ), mesothelioma (MESO), head and neck squamous cell carcinoma (HNSC), and colon adenocarcinoma (COAD). In addition, CDK1 expression correlated with immune cell infiltrating levels, such as M0, M1, or M2 macrophages, memory CD4 T cells, T follicular helper cells, and naive B cells. Our data showed that CDK1 was remarkably correlated with 47 immune-related and immune checkpoint genes in many cancer types. Furthermore, CDK1 was up-regulated in gastrointestinal tumor samples, especially in gastric cancer and intestinal cancer. CDK1 was positively correlated with IDO1 in gastric cancer and PD-1 in intestinal cancer. CONCLUSION: Taken together, our data demonstrated the roles of CDK1 in oncogenesis and metastasis in pan-cancer. Thus, CDK1 is a potential prognostic biomarker and a target for tumor immunotherapy.

The cause and effect of gut microbiota in development of inflammatory disorders of the breast.

BACKGROUND: Inflammatory disorders of the breast (IDB) damages the interests of women and children and hinders the progress of global health seriously. Several studies had offered clues between gut microbiota (GM) and inflammatory disorders of the breast (IDB). The gut-mammary gland axis also implied a possible contribution of the GM to IDB. However, the causality between them is still elusive. METHODS: The data of two-sample Mendelian randomization (MR) study related to the composition of GM (n = 18,340) and IDB (n = 177,446) were accessed from openly available genome-wide association studies (GWAS) database. As the major analytical method, inverse variance weighted (IVW) was introduced and several sensitive analytical methods were conducted to verify results. RESULTS: Inverse variance weighted revealed Eubacterium rectale group (OR = 1.87, 95% CI: 1.02-3.43, p = 4.20E-02), Olsenella (OR = 1.29, 95% CI: 1.02-1.64, p = 3.30E-02), Ruminiclostridium-6 (OR = 1.53, 95% CI: 1.08-2.14, p = 1.60E-02) had an anti-protective effect on IDB. Peptococcus (OR = 0.75, 95% CI: 0.60-0.94, p = 1.30E-02) had a protective effect on IDB. The results were credible through a series of test. CONCLUSIONS: We revealed causality between IDB and GM taxa, exactly including Ruminiclostridium-6, Eubacterium rectale group, Olsenella and Peptococcus. These genera may become novel biomarkers and supply new viewpoint for probiotic treatment. However, these findings warrant further test owing to the insufficient evidences.

5-Hydroxymethylfurfural induces mice frailty through cell senescence-associated sarcopenia caused by chronic inflammation.

Objective: 5-Hydroxymethylfurfural (5-HMF) is an important component of air pollution, confirmed to be a risk factor for pulmonary inflammation. However, its association with general health is unknown. This article aimed to clarify the effect and mechanism of 5-HMF in the occurrence and aggravation of frailty in mice by investigating whether exposure to 5-HMF was linked to the occurrence and aggravation of mice frailty. Methods: Twelve male C57BL/6 mice (12-month-old, 38 ± 1 g) were randomly divided into the control group and the 5-HMF group. The 5-HMF group was treated with 5-HMF (1 mg/kg/day, respiratory exposure) for 12 months, whereas the control group was treated with equal amounts of sterile water. After the intervention, the ELISA method was used to detect the serum inflammation level of the mice, and the physical performance and frail status were evaluated using a Fried physical phenotype-based assessment tool. The differences in the body compositions were calculated from their MRI images, and the pathological changes in their gastrocnemius muscle were revealed using the H&E staining. Furthermore, the senescence of skeletal muscle cells was evaluated by measuring the expression levels of senescence-related proteins by the western blotting. Results: In the 5-HMF group, serum inflammatory factors IL-6, TNF-α, and CRP levels were significantly raised (p < 0.01). Mice in this group had higher frailty scores and significantly reduced grip strength (p < 0.001), slower weight gains, less WVgastrocnemius muscle masses, and lower sarcopenia indices (SI). In addition, the cross-sectional areas of their skeletal muscles were reduced, and the levels of their cell senescence-related proteins (p53, p21, p16, SOD1, SOD2, SIRT1, SIRT3) were considerably altered (p < 0.01). Conclusion: 5-HMF may induce chronic and systemic inflammation, which in turn accelerates the progression of the frailty of mice through cell senescence.

Exposure to irregular microplastic shed from baby bottles activates the ROS/NLRP3/Caspase-1 signaling pathway, causing intestinal inflammation.

Irregularly shaped microplastics (MPs) released from infant feeding bottles (PP-IFBs) may exhibit increased cytotoxicity, in contrast to the commonly studied spherical MPs. This study presents an initial analysis of the thermal-oxidative aging process of plastic shedding from feeding bottles, and investigates the inflammatory response induced by these atypical MPs in human intestinal cells (Caco-2). The PP-IFBs' surface displayed non-uniform white patches and increased roughness, revealing substantial structural alteration and shedding, especially during actions such as shaking, boiling water disinfection, and microwave heating. FT-IR and 2D-COS analyses revealed that oxygen targeted the C-H and C-C bonds of polypropylene molecular chain, producing RO· and ·OH, thereby hastening polypropylene degradation. When human intestinal cells were exposed to MPs from PP-IFBs, oxidative stress was triggered, resulting in lowered glutathione levels, augmented reactive oxygen species (ROS), and heightened lipid peroxidation. Elevated levels of pro-inflammatory cytokines (IL-6 and TNFα) signified an active inflammatory process. The inflammatory response was notably more intense when exposed to MPs released through boiling water disinfection and microwave heating treatments, primarily due to the larger quantity of MPs released and their higher proportion of smaller particles. Furthermore, the NLRP3 inflammasome was identified as critical in initiating this inflammatory chain reaction due to the mitochondrial ROS surge caused by MPs exposure. This was further validated by inhibitor studies, emphasizing the role of the ROS/NLRP3/Caspase-1/IL-1ß signaling pathway in in promoting intestinal inflammation. Therefore, swift actions are recommended to protect infants against the potential health effects of MPs exposure.

A novel approach to predict the comprehensive EROD potency: Mechanism-based curve fitting of CYP1A1 activity by PAHs.

Cytochrome P450 1A1 (CYP1A1) plays critical roles in polycyclic aromatic hydrocarbon (PAH) toxicity, including DNA adduction and ROS generation. Therefore, CYP1A1 activity quantified by the 7-ethoxyresorufin-O-deethylase (EROD) assay (named EROD potency) has been considered a typical biomarker of PAH exposure and toxicity. The EROD dose-response curve always presents a biphasic style, increasing at low concentrations and decreasing at high concentrations of PAHs, but relative effect potency (REP) commonly used in PAH risk assessment is only involved in the increasing phase. In this study, a full bell-shaped EROD curve fitting formula Eq. (1) was obtained by considering both CYP1A1 mRNA induction and enzyme inhibition to completely assess the EROD potency of PAHs. Correspondingly, in silico models of QSAR and docking methods successfully predicted the full EROD curves of PAHs, and the structure-activity relationship indicated that PAHs with heavy molecular weight and large diameter showed stronger EROD potency. Further EROD potency with predicted curve parameters (EC50,ind and area index) was confirmed by the reported REP (R2 = 0.697-0.977) and experimental data from human and mouse cells (R2 = 0.700-0.804). This study provides a novel curve fitting for the EROD dose-response relationship and a prediction model for PAH EROD potency.

Mutagenicity risk prediction of PAH and derivative mixtures by in silico simulations oriented from CYP compound I-mediated metabolic activation.

PAHs and their derivatives are the main sources of mutagenicity and carcinogenicity in airborne particular matter and cause serious public health and environmental problems. Risk assessment is challenging due to the mixed nature and deficiency of toxicity data of most PAHs and their derivatives. Cytochrome P450 enzymes (CYPs) play important roles in PAH-induced carcinogenicity via metabolic activation, and CYP conformations with compound I structures strongly influence metabolic sites and metabolite species. In this study, complexes of BaP with CYP1A1, CYP1B1 or CYP2C19 compound I were successfully simulated by QM/MM methods and verified by metabolic clearance, and the mutagenicity of chemicals was then predicted by the BaP-7,8-epoxide-related metabolic conformation fitness (MCF) approach, which was validated by Ames tests, showing satisfying accuracy (R2 = 0.46-0.66). Furthermore, a prediction model of the mutagenicity risk of PAH and derivative mixtures was established based on the relative potential factor (RPF) approach and the RPF calculated from the mathematical relationship between the minimum MCF (MCFmin) and RPF, which was successfully validated by the mutagenesis of PAH and derivative mixture mimic-simulating PM2.5 samples collected in eastern China. This study provides fast reliable tools for assessing risk of the complex components of environmental PAHs and their derivatives.

Identification of structural properties influencing the metabolism of polycyclic aromatic hydrocarbons by cytochrome P450 1A1.

Cytochrome P450 1A1 (CYP1A1) has served as a known metabolic enzyme that mediates the carcinogenesis of polycyclic aromatic hydrocarbons (PAHs). However, the structural mechanism involved in the metabolic capacity remains unclear. In this study, thirty-three calculated properties representing the physicochemical and electronic properties of PAH and PAH-CYP1A1 interactions were utilized to identify the key structural properties that affect metabolic processes, including binding ability, metabolic clearance, and mutagenicity, using a quantitative structure-activity relationship (QSAR) strategy combined with docking methods, QM/MM calculations and ab initio calculations. van der Waals interactions (glide vdw) appeared to be important for PAH binding to CYP1A1 and were mainly affected by the molecular weight and hydrophobic structures of PAHs. Interaction features between PAHs and heme, including the distance between iron and carbons of PAHs (Fe_Cmin) and heme vdw, coordinately influence the metabolic clearance of PAHs. Furthermore, the electronic properties (ESP neg variance) appeared to be critical for the mutagenicity of PAHs by CYP1A1 through influencing epoxide metabolite formation. The QSAR models with these key properties provide a new perspective on the structural mechanism of PAH metabolism and provide a useful in silico tool for screening, classifying and predicting PAHs for their metabolism-related toxicities and risk assessment in the environment.

Expression of Four Autophagy-Related Genes Accurately Predicts the Prognosis of Gastrointestinal Cancer in Asian Patients.

Gastrointestinal (GI) cancers are among the most fatal diseases in the world. Numerous studies have demonstrated the relationship between autophagy and development of gastrointestinal cancers. However, whether autophagy-related genes can predict prognosis of GI cancers in individuals of Asian ancestry has not been defined. This study, evaluated the prognostic value of autophagy-related genes in gastrointestinal cancer. Expression profile of autophagy-related genes for 296 gastrointestinal cancer patients of Asian ancestry was downloaded from the TCGA database (TCGA-LIHC, TCGA-STAD, TCGA-ESCA, TCGA-PAAD, TCGA-COAD, TCGA-CHOL, and TCGA-READ). The prognostic value of the autophagy-related genes was evaluated using univariate Cox, LASSO, and multivariate Cox regression analyses. The risk score of the autophagy-related gene signature was calculated to assess its predictive prognostic value for GI cancers. Forty-seven differentially expressed autophagy-related genes, in Asian patients with gastrointestinal cancers, were identified. Of the 47 genes, 4 were associated with prognosis of GI cancer (SQSTM1, BIRC5, NRG3, and CXCR4). A prognostic model for GI cancer, based on the expression of the above 4 genes in the training set, showed that cancer patients were stratified into high-risk and low-risk groups (P < 0.05). The utility of the model for overall survival (OS) of GI cancer patients was consistent across the entire set, training set, and test set (entire set: P = 4.568 × 10-4; train set: P = 5.718 × 10-3; test set: P = 3.516 × 10-2). The sensitivity and specificity of the ROC curve of the above prognostic model in predicting the 5-year prognosis of GI cancer was satisfactory (entire set: 0.728; train set: 0.727; test set: 0.733). Analysis of clinical samples validated the overexpression of the 4 genes (SQSTM1, BIRC5, NRG3, and CXCR4) in tumor tissues relative to paired normal tissues, consistent with bioinformatic findings. Expression of the 4 autophagy-related genes (SQSTM1, BIRC5, NRG3, and CXCR4) can accurately predict the prognosis of gastrointestinal tumors in Asian patients.

Fenvalerate triggers Parkinson-like symptom during zebrafish development through initiation of autophagy and p38 MAPK/mTOR signaling pathway.

Fenvalerate (FEN), one of the most used synthetic pyrethroids, has the potential to interfere with human neural function. However, far too little attention was paid to the mechanism of FEN-induced neurotoxicity. Thus we exposed zebrafish to FEN from 4 to 120 h post fertilization (hpf), and analyzed the morphology and behavior of zebrafish. Our results showed that FEN decreased the survival rate of zebrafish, with increased malformation rates and abnormal behaviors. Furthermore, we found typical parkinson-like symptoms in FEN-exposed zebrafish with increases in parkinson's disease (PD), ubiquitin, and Lewy bodies-relevant genes. We also observed the loss of dopaminergic neurons in both FEN-exposed zebrafish and PC12 cells, which were all associated with PD-like symptoms. Besides, FEN activated autophagy by the enhanced expressions of p-mTOR, and LC3-II but the reduction of p62. Further, FEN initially activated p-p38 MAPK followed by p-mTOR, which triggered the transcription of genes responsible for autophagy process and prompted the Lewy bodies neuron generation leading to the PD-like symptoms. This process was inhibited by both 3-methyladenine (3-MA, an autophagy inhibitor) and SB203580 (a p38 MAPK selective inhibitor) in zebrafish and PC12 cells. These results suggest that FEN might cause parkinson-like symptom during zebrafish development through induction of autophagy and activation of p38 MAPK/mTOR signaling pathway. The study revealed the potential mechanism of FEN-induced neurotoxicity and should give new insights into a significant environmental risk factor of developing parkinson's disease.

Rno-miR-224-5p contributes to 2,2',4,4'-tetrabromodiphenyl ether-induced low triiodothyronine in rats by targeting deiodinases.

Hypothyroidism is commonly associated with substantial adverse impacts on human health, and polybrominated diphenyl ether (PBDE), a kind of classic thyroid hormone disruptor, was speculated to be a potential environmental factor, but its effect on thyroxine metabolism has received little attention. In the present study, we investigated the role and mechanism of rno-miR-224-5p in deiodinase-mediated thyroxine metabolism in rats treated with 2,2',4,4'-tetrabromodiphenyl ether (BDE47), a predominant PBDE congener in humans. BDE47 decreased plasma triiodothyronine (T3) and thyroxine (T4) and increased reverse T3 (rT3) in the rats, and the expression of type 1 deiodinase (DIO1) and type 3 deiodinase (DIO3) increased in both the rats and H4-II-E cells. Rno-miR-224-5p was predicted to target dio1 instead of dio3, according to the TargetScan, miRmap.org and microRNA.org databases. Experiments showed that the rno-miR-224-5p level was decreased by BDE47 in a dose-dependent manner and confirmed that rno-miR-224-5p downregulated both DIO1 and DIO3 in the H4-II-E cells and in the rats, as determined using mimics and an inhibitor of rno-miR-224-5p. Furthermore, DIO1 was observed to be a direct functional target of rno-miR-224-5p, whereas DIO3 was indirectly regulated by rno-miR-224-5p via the phosphorylation of the MAPK/ERK (but not p38 or JNK) pathway. Reportedly, DIO1 and DIO3 act principally as inner-ring deiodinases and are responsible for the conversion of T4 to rT3, but not to T3, and the final clearance of thyroxine (mainly in the form of T2). Our results demonstrated that BDE47 induced low levels of T3 conversion through DIO1 and DIO3, which were regulated by rno-miR-224-5p. The findings suggest a novel additional mechanism of PBDE-induced thyroxine metabolism disorder that differs from that of PBDEs as environmental thyroid disruptors.

Isoliquiritigenin as an antioxidant phytochemical ameliorates the developmental anomalies of zebrafish induced by 2,2',4,4'-tetrabromodiphenyl ether.

2,2',4,4'-Tetrabromodiphenyl ether (BDE47) is the most abundant PBDE congeners in biological samples. It has strong tendencies to bioaccumulate and potentially endangers development of mammals through oxidative stress. Isoliquiritigenin (ISL), an emerging natural chalcone-type flavonoid, possesses various biological and pharmacological properties, including antioxidant, anti-allergic, anti-inflammatory, anti-tumor and estrogenic activities. The purpose of the study is to explore the antioxidant effect of ISL on the amelioration of developmental anomalies induced by BDE47. Zebrafish (Danio rerio) embryos were exposed to BDE47 (1 and 10 µM) and/or ISL (4 µM) for 4 to 120 hours post fertilization (hpf), and the morphology, development, behavior, oxidative stress status and related genes expression were assessed. The results showed that BDE47 contributed to dose-dependent growth retardation and deformities, including delayed hatching, spinal curvature, reduced body length, increased death rate, aberrant behaviors and impaired dark-adapted vision, which were significantly mitigated by ISL. Besides, ISL ameliorated excessive ROS accumulation, and exaggerated the expressions of apoptosis-related genes p53, Bcl-2, caspase 3 and caspase 9 induced by BDE47, suggesting that ISL protected zebrafish from the developmental toxicity of BDE47 by inactivation of programmed apoptosis and activation of antioxidant signaling pathways. Taken together, developing ISL as a dietary supplement might be a promising preventive strategy for the amelioration of developmental toxicity induced by environmental pollutants.

An assessment of factors associated with quality of randomized controlled trials for smoking cessation.

To reduce smoking-related diseases, a research priority is to develop effective interventions for smoking cessation, and evidence from randomized controlled trials (RCTs) is usually considered to be the most valid. However, findings from RCTs may still be misleading due to methodological flaws. This study aims to assess the quality of 1083 RCTs of smoking cessation interventions in 41 relevant Cochrane Systematic Reviews (CSRs). Logistic regression analysis was performed to identify significant variables associated with the quality of RCTs. It was found that evidence for smoking cessation from RCTs was predominantly from high income countries, and the overall quality was high in only 8.6% of the RCTs. High quality RCTs tended to have a larger sample size, to be more recently published, and conducted in multiple countries belonging to different income categories. In conclusion, the overall quality of RCTs of smoking cessation interventions is far from perfect, and more RCTs in less developed countries are required to generate high grade evidence for global tobacco control. Collaboration between researchers in developed and less developed countries should be encouraged.