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Introduction: Intracerebral hemorrhage (ICH) often triggers oxidative stress through reactive oxygen species (ROS). Transforming growth factor-bactivated kinase 1 (TAK1) plays a pivotal role in regulating oxidative stress and inflammation across various diseases. 5Z-7-Oxozeaenol (OZ), a specific inhibitor of TAK1, has exhibited therapeutic effects in various conditions. However, the impact of OZ following ICH and its underlying molecular mechanisms remain elusive. This study aimed to explore the possible role of OZ in ICH and its underlying mechanisms by inhibiting oxidative stress-mediated pyroptosis. Methods: Adult male Sprague-Dawley rats were subjected to an ICH model, followed by treatment with OZ. Neurobehavioral function, blood-brain barrier integrity, neuronal pyroptosis, and oxidative stress markers were assessed using various techniques including behavioral tests, immunofluorescence staining, western blotting, transmission electron microscopy, and biochemical assays. Results: Our study revealed that OZ administration significantly inhibited phosphorylated TAK1 expression post-ICH. Furthermore, TAK1 blockade by OZ attenuated blood-brain barrier (BBB) disruption, neuroinflammation, and oxidative damage while enhancing neurobehavioral function. Mechanistically, OZ administration markedly reduced ROS production and oxidative stress by facilitating nuclear factor-erythroid 2-related factor 2 (NRF2) nuclear translocation. This was accompanied by a subsequent suppression of the NOD-like receptor protein 3 (NLRP3) activation-mediated inflammatory cascade and neuronal pyroptosis. Discussion: Our findings highlight that OZ alleviates brain injury and oxidative stress-mediated pyroptosis via the NRF2 pathway. Inhibition of TAK1 emerges as a promising approach for managing ICH. [ABSTRACT FROM AUTHOR]

Nitrosamines were a class of important environmental carcinogens associated with digestive tract neoplasms. As the early toxic effect of nitrosamines, inflammatory response participated in the malignant transformation of cells and promoted the occurrence and development of tumors. However, the role of NLRP3 inflammasome in the nitrosamines-induced inflammatory response was unclear. In this study, the human esophageal epithelial cells (Het-1A) were used to explore potential mechanisms of the activation of NLRP3 inflammasome under co-exposure to nine nitrosamines commonly found in drinking water at the doses of 0, 4, 20, 100, 500, and 2500 ng/mL. The results showed that nitrosamines stimulated activation of the NLRP3 inflammasome and induced cellular oxidative damage in a dose-dependent manner. Pretreatment of reactive oxygen species scavenger N-acetyl-L-cysteine (NAC), particularly mitochondrial reactive oxygen species (mtROS) scavengers MitoTEMPO, effectively inhibited the activation of NLRP3 inflammasome, suggesting that nitrosamines could mediate the activation of NLRP3 inflammasome via mtROS. Furthermore, we found that nitrosamines co-exposure also promoted cell pyroptosis through the NLRP3/caspase-1/GSDMD pathway, which was demonstrated by adding the caspase-1 inhibitor Z-YVAD-FMK and constructing NLRP3 downregulated Het-1A cell line. This study revealed the underlying mechanism of the activation of NLRP3 inflammasome initiated by nitrosamines co-exposure and provided new perspectives on the toxic effects of nitrosamines. [ABSTRACT FROM AUTHOR]

Objective: This study aims to systematically evaluate the curative efficacy of different acupuncture methods in the treatment of obesity combined with insulin resistance in randomized clinical trials (RCTs) by network meta-analysis. Methods: Four Chinese databases (CNKI, WanFang Data, VIP, and SinoMed) and four English databases (PubMed, Embase, the Cochrane Library, and www. clinicaltrial.gov) were electronically searched to identify qualified studies. Two reviewers independently screened the literature in accordance with the inclusion/exclusion criteria by EndNote 20 software and extracted data by ADDIS1.16.8 software, and then the risk of bias of the included studies were evaluated by the Cochrane tool. Network meta-analysis was performed by Stata 15.1 software. The primary outcomes included fasting blood glucose (FBG), fasting serum insulin (FINS), homeostasis model assessment--insulin resistance (HOMA-IR), and body mass index (BMI). The secondary outcomes included waistline, waist-hip ratio, triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL). Results: Five RCTs with a total of 410 patients with obesity combined with insulin resistance were included. The results of the network meta-analysis showed that, compared with the control group, three kinds of acupuncture methods (electropuncture, acupoint catgut embedding, and acupuncture point patch) had significant efficacy in reducing FBG [electropuncture (MD = -0.44, 95% CI: -0.83, -0.05) and acupoint catgut embedding (MD = -0.36, 95% CI: -0.51, -0.21)], FINS [electropuncture (MD = -6.17, 95% CI: -9.69, -2.65), acupoint catgut embedding (MD = -5.87, 95% CI: -6.92, -4.82), and acupuncture point patch (MD = -5.86, 95% CI: -11.40, -0.32)], HOMA-IR[electropuncture(MD=-1.59,95%CI: -2.73, -0.45)and acupoint catgut embedding (MD =-0.91, 95% CI: -1.07, -0.75)], BMI [electropuncture (MD = -1.68, 95% CI: -2.70, -0.66), acupoint catgut embedding (MD = -3.39, 95% CI: -4.38, -2.40), and acupuncture point patch [MD = -2.90, 95% CI: -4.93, -0.87)], andwaistline [electropuncture (MD = -5.49, 95% CI: -8.56, -2.42) and acupoint catgut embedding (MD=-4.91, 95%CI: -7.51, -2.31)] inobese patients with insulin resistance, suggesting that their efficacy was better than that of the westernmedicine group insome of theoutcomeindicators. For the index related to blood lipid, the efficacy of electropuncture was significantly better than behavioral therapy and western medicine. Except that acupoint catgut embedding was superior to electroacupuncture in reducing the BMI, there was no statistically significant difference in efficacy among the three acupuncture methods. Conclusions: The results showed that the therapeutic effect of acupuncture methods was superior to conventional western treatment alone. Acupuncture methods could serve as an alternative or adjunctive treatment in obese patients with insulin resistance. [ABSTRACT FROM AUTHOR]

Benzene, a known occupational and environmental contaminant, has been recognized as the hematotoxin and human carcinogen. Lipids have a variety of important physiological functions and the abnormal lipid metabolism has been reported to be closely related to the occurrence and development of many diseases. In the present study, we aim to utilize LC-MS/MS lipidomic platform to identify novel biomarkers and provide scientific clues for mechanism study of benzene hematotoxicity. Results showed that a total of 294 differential metabolites were obtained from the comparison of benzene-treated group and control group. The glycerophospholipid pathway was altered involving the down-regulation of the levels of phosphatidylcholine and phosphatidylserine. In addition, phosphatidylethanolamine (PE) and 1-Acyl-sn-glycero-3-phosphocholine levels were increased in benzene-treated group. Based on the relationship between PE and autophagy, we then found that effective biomarker of autophagy, Beclin1 and LC3B, were increased remarkably. Furthermore, following benzene treatment, significant decreases in glucosylceramide (GlcCer) and phytosphingosine (PHS) levels in sphingolipid pathway were observed. Simultaneously, the levels of proliferation marker (PCNA and Ki67) and apoptosis regulator (Bax and Caspase-3) showed clear increases in benzene-exposed group. Based on our results, we speculate that disturbances in glycerophospholipid pathway play an important role in the process of benzene-induced hematopoietic toxicity by affecting autophagy, while sphingolipid pathway may also serve as a vital role in benzene-caused toxicity by regulating proliferation and apoptosis. Our study provides basic study information for the future biomarker and mechanism research underlying the development of benzene-induced blood toxicity. [ABSTRACT FROM AUTHOR]

Background: Cervical cancer (CC) is a common gynecological malignancy in women worldwide. Evidence suggests that long non-coding RNAs (lncRNAs) can be used as biomarkers in patients with CC. However, prognostic biomarkers for CC are still lacking. The aim of our study was to find lncRNA biomarkers which are able to predict prognosis in CC based on the data from The Cancer Genome Atlas (TCGA). Methods: The patients were divided into three groups according to FIGO stage. Differentially expressed lncRNAs were identified in CC tissue compared to adjacent normal tissues based on a fold change >2 and <0.5 at P < 0.05 for up- and downregulated lncRNA, respectively. The relationship between survival outcome and lncRNA expression was assessed with univariate and multivariate Cox proportional hazards regression analysis. We constructed a risk score as a method to evaluate prognosis. We used receiver operating characteristic (ROC) curve and the area under curve (AUC) analyses to assess the diagnostic value of a two-lncRNA signature. We detected the expression levels of the two lncRNAs in 31 pairs of newly diagnosed CC specimens and paired adjacent non-cancerous tissue specimens, and also in CC cell lines. Finally, the results were statistically compared using t-tests. Results: In total, 289 RNA sequencing profiles and accompanying clinical data were obtained. We identified 49 differentially expressed lncRNAs, of which two related to overall survival (OS) in CC patients. These two lncRNAs (ILF3-AS1 and RASA4CP) were found together as a single prognostic signature. Meanwhile, the prognosis of patients with low-risk CC was better and positively correlated with OS (P < 0.001). Further analysis showed that the combined two-lncRNA expression signature could be used as an independent biomarker to evaluate the prognosis in CC. qRT-PCR results were consistent with TCGA, confirming downregulated expression of both lncRNAs. Furthermore, upon ROC curve analysis, the AUC of the combined lncRNAs was greater than that of the single lncRNAs alone (0.723 vs 0.704 and 0.685), respectively; P < 0.05. Conclusions: Our study showed that the two-lncRNA signature of ILF3-AS1 and RASA4CP can be used as an independent biomarker for the prognosis of CC, based on bioinformatic analysis. [ABSTRACT FROM AUTHOR]

Objectives. To comprehensively analyse the global scientific outputs of hepatocellular carcinoma (HCC) research. Methods. Data of publications were downloaded from the Web of Science Core Collection. We used CiteSpace IV and Excel 2016 to analyse literature information, including journals, countries/regions, institutes, authors, citation reports and research frontiers. Results. Until March 31, 2018, a total of 24,331 papers in HCC research were identified as published between 2008 and 2017. Oncotarget published the most papers. China contributed the most publications and the United States occupied leading positions in H-index value and the number of ESI top papers. Llovet JM owned the highest co-citations. The keyword ''transarterial chemoembolization'' ranked first in the research front-line. Conclusions. The amount of papers published in HCC research has kept increasing since 2008. China showed vast progress in HCC research, but the United States was still the dominant country. Transarterial chemoembolization, epithelial-mesenchymal transition, and cancer stem cell were the latest research frontiers and should be paid more attention. [ABSTRACT FROM AUTHOR]

MicroRNA (miRNA) clusters are expressed universally across different types of organisms, and an accumulating number of studies have demonstrated that miRNA clusters function more efficiently compared with single miRNAs during the development of certain cancer types. miRNA clusters may have increased stability and reliability over individual miRNAs as diagnostic or therapeutic biomarkers. In the present study, the expression levels of mature miRNAs within the miR-144/451 cluster were examined using stem-loop reverse transcription-quantitative polymerase chain reaction in 102 patients pathologically diagnosed with esophageal carcinoma. Bioinformatics tools were used to identify a possible miRNA-mediated network of the miR-144/451 cluster. The expression levels of hsa-miR-451a, hsa-miR-144-3p and hsa-miR-144-5p in tumor tissues were significantly lower compared with those in adjacent non-tumor tissues (P<0.05). Pearson correlation analysis demonstrated that the expression levels of individual miR-144/451 cluster members were correlated with each other, except for the pair of hsa-miR-144-3p and hsa-miR-4732-3p. In particular, hsa-miR-144-5p expression was highly associated with hsa-miR-4732-5p and hsa-miR-451a expression levels, with correlation coefficients of 0.729 and 0.608, respectively. Furthermore, the low expression levels of hsa-miR-144-3p [odds ratio (OR), 0.85; P<0.05] and hsa-miR-144-5p (OR, 0.84; P<0.05) were determined to be risk factors for esophageal carcinoma development. Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that miRNAs forming the miR-144/451 cluster may cooperate to regulate the cell cycle. Therefore, the miR-144/451 cluster may serve an important role in the progression of esophageal carcinoma and may be considered as a biomarker for the detection of esophageal carcinoma at an early stage. [ABSTRACT FROM AUTHOR]

miR-218, consisting of miR-218-1 at 4p15.31 and miR-218-2 at 5q35.1, was significantly decreased in esophageal squamous cell carcinoma (ESCC) in our previous study. The aim of this study was to determine whether aberrant methylation is associated with miR-218 repression. Bisulfite sequencing analysis (BSP), methylation specific PCR (MSP), and 5-aza-21-deoxycytidine treatment assay were applied to determine the methyaltion status of miR-218 in cells and clinical samples. In vitro assays were performed to explore the role of miR-218. Results showed that miR-218-1 was significantly CpG hypermethylated in tumor tissues (81%, 34/42) compared with paired non-tumor tissues (33%, 14/42) (p < 0.05). However, no statistical difference was found in miR-218-2. Accordingly, expression of miR-218 was negatively correlated with miR-218-1 methylation status (p < 0.05). After demethylation treatment by 5-aza-21-deoxycytidine, there was a 2.53-and 2.40-fold increase of miR-218 expression in EC109 and EC9706, respectively. miR-218 suppressed cell proliferation and arrested cells at G1 phase by targeting 31 untranslated region (31UTR) of roundabout guidance receptor 1 (ROBO1). A negative correlation was found between miR-218 and ROBO1 mRNA expression in clinical samples. In conclusion, our results support that aberrant CpG hypermethylation at least partly accounts for miR-218 silencing in ESCC, which impairs its tumor-suppressive function. [ABSTRACT FROM AUTHOR]

Benzene is a common environmental pollutant that causes hematological alterations. MicroRNAs (miRNAs) may play a role in benzene-induced hematotoxicity. In this study, C57BL/6 mice showed significant hematotoxicity after exposure to 150 mg/kg benzene for 4 weeks. Benzene exposure decreased not only the number of cells in peripheral blood but also hematopoietic progenitor cells in the bone marrow. Meanwhile, RNA from Lin- cells sorted from the bone marrow was applied to aberrant miRNA expression profile using Illumina sequencing. We found that 5 miRNAs were overexpressed and 45 miRNAs were downregulated in the benzene exposure group. Sequencing results were confirmed through qRT-PCR. Furthermore, we also identified five miRNAs which significantly altered in Lin-c-Kit+ cells obtained from benzene-exposed mice, including mmu-miR-34a-5p; mmu-miR-342-3p; mmu-miR-100-5p; mmu-miR-181a-5p; and mmu-miR-196b-5p. In summary, we successfully established a classical animal model to induce significant hematotoxicity by benzene injection. Benzene exposure may cause severe hematotoxicity not only to blood cells in peripheral circulation but also to hematopoietic cells in bone marrow. Benzene exposure also alters miRNA expression in hematopoietic progenitor cells. This study suggests that benzene induces alteration in hematopoiesis and hematopoiesis-associated miRNAs. [ABSTRACT FROM AUTHOR]

Little is known about the effect on spermiogenesis induced by microcystin-leucine arginine (MC-LR), even though such data are very important to better elucidate reproductive health. In the current work, with the aid of nematode Caenorhabditis elegans (C. elegans) as an animal model, we investigated the defects on spermiogenesis induced by MC-LR. Our results showed that MC-LR exposure induced sperm morphology abnormality and caused severe defects of sperm activation, trans-activation, sperm behavior and competition. Additionally, the expression levels of spe-15 were significantly decreased in C. elegans exposed to MC-LR lower than 16.0 μg/L, while the expression levels of spe-10 and fer-1 could be significantly lowered in C. elegans even exposed to 1.0 μg/L of MC-LR. Therefore, the present study reveals that MC-LR can induce adverse effects on spermiogenesis, and those defects of sperm functions may be induced by the decreases of spe-10, spe-15 and fer-1 gene expressions in C. elegans. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the biofunctions of microRNA (miR)-125b on lung cancer cells. A miR genechip array was used to examine the differential expression of miRs between 95D lung cancer cells and 16 human bronchial epithelial (HBE) cells. Overexpression of miR-125b was observed in the cell lines and in the lung carcinoma tissues compared with the adjacent tissues, confirmed using reverse transcription quantitative polymerase chain reaction. Bioinformatic analysis of miR-125b was also performed, including target prediction, gene ontology and pathway analysis. MTT, flow cytometry and Transwell assays were also used to examine the effect of downregulated miR-125b on the proliferation, apoptosis, invasive ability and cell cycle of 95D cells. Significant differences were observed in the expression of 45 miRs in the 95D cells compared with those in 16HBE cells and the expression of miR-125b was significantly higher in 95D cells compared with that in 16HBE cells as well as in lung tumor tissues compared with that in adjacent tissues. In addition, inhibition of the expression of miR-125b in 95D cells induced apoptosis, G1/S phase arrest and reduction of their invasive ability. In addition, bioinformatics software predicted that miR-125b was involved in the regulation of several pathways associated with cancer, including the transforming growth factor-β, Wnt and mitogen-activated protein kinase signaling pathways. These data indicated for the first time, to the best of our knowledge, that miR-125b may function as an oncogene in lung cancer. [ABSTRACT FROM AUTHOR]

The potential immune effects of titanium dioxide nanoparticles (nano-TiO2) are raising concern. Our previous study verified that nano-TiO2 induce local immune response in lung tissue followed by intratracheal instillation administration. In this study, we aim to evaluate the systemic immune effects of nano-TiO2. Sprague Dawley rats were treated by intratracheal instillation with nano-TiO2 at doses of 0.5, 4, and 32 mg/kg body weight, micro-TiO2 with 32 mg/kg body weight and 0.9% NaCl, respectively. The exposure was conducted twice a week, for four consecutive weeks. Histopathological immune organs from exposed animals showed slight congestion in spleen, generally brown particulate deposition in cervical and axillary lymph node. Furthermore, immune function response was characterized by increased proliferation of T cells and B cells following mitogen stimulation and enhanced natural killer (NK) cell killing activity in spleen, accompanying by increased number of B cells in blood. No significant changes of Th1-type cytokines (IL-2 and INF-ɣ) and Th2-type cytokines (TNF-ɑ and IL-6) were observed. Intratracheal exposure to nano-TiO2 may be one of triggers to be responsible for the systemic immune response. Further study is needed to confirm long-lasting lymphocyte responses and the potential mechanisms. [ABSTRACT FROM AUTHOR]

Benzene is identified as a carcinogen. Continued exposure of benzene may eventually lead to damage to the bone marrow, accompanied by pancytopenia, aplastic anemia or leukemia. This paper explores the variations of endogenous metabolites to provide possible clues for the molecular mechanism of benzene-induced hematotoxicity. Liquid chromatography coupled with time of flight-mass spectrometry (LC-TOF-MS) and principal component analysis (PCA) was applied to investigate the variation of endogenous metabolites in bone marrow cells and plasma of male C3H/He mice. The mice were injected subcutaneously with benzene (0, 300, 600 mg/day) once daily for seven days. The body weights, relative organ weights, blood parameters and bone marrow smears were also analyzed. The results indicated that benzene caused disturbances in the metabolism of oxidation of fatty acids and essential amino acids (lysine, phenylalanine and tyrosine) in bone marrow cells. Moreover, fatty acid oxidation was also disturbed in plasma and thus might be a common disturbed metabolic pathway induced by benzene in multiple organs. This study aims to investigate the underlying molecular mechanisms involved in benzene hematotoxicity, especially in bone marrow cells. [ABSTRACT FROM AUTHOR]

This study was conducted to obtain the basic data of two common odorants--geosmin and 2-methylisoborneol (GSM and 2-MIB)--in environmental water. More specifically, the headspace solid-phase microextraction coupled to gas chromatography mass spectrometry (HS-SPME/GC-MS) was applied to determine the levels of GSM and 2-MIB in water samples, and the samples were collected depending on water sources, conventional treatment processes, and seasons. The significant difference was shown for the 2-MIB levels of source water (P < 0.05), the concentrations of GSM and 2-MIB decreased significantly as treatment process of tap water moved forward (P < 0.0001), and the significant differences for the levels of GSM and 2-MIB were observed among three sampling periods (P < 0.01). The levels of GSM and 2-MIB in all water samples were lower than 10ngL-1, the odor threshold concentration (OTC), and the conventional treatment process plays a significant role in removing odorants in tap water. [ABSTRACT FROM AUTHOR]

The pressing issue of earthy andmusty odor compounds in natural waters, which can affect the organoleptic properties of drinking water, makes it a public health concern. A simple and sensitivemethod for simultaneous analysis of five odorants in environmental water was developed by headspace solid-phase microextraction (HS-SPME) coupled to chromatography-mass spectrometry (GCMS), including geosmin (GSM) and 2-methylisoborneol (2-MIB), as well as dimethyl trisulfide (DMTS), β-cyclocitral, and β- ionone. Based on the simplemodification of originalmagnetic stirrer purchased fromCORNING(USA), the five target compounds can be separated within 23 min, and the calibration curves showgood linearitywith a correlation coefficient above 0.999 (levels = 5). The limits of detection (LOD) are all below 1.3 ng L-1, and the relative standard deviation (%RSD) is between 4.4% and 9.9% (n = 7) and recoveries of the analytes fromwater samples are between 86.2% and 112.3%. In addition, the storage time experiment indicated that the concentrations did not change significantly for GSMand 2-MIB if theywere stored in canonical environment. In conclusion, the method in this study could be applied for monitoring these five odorants in natural waters. [ABSTRACT FROM AUTHOR]

Epidemiological studies indicated that esophageal squamous-cell carcinoma (ESCC) is still one of the most common causes of cancer incidence in the world. Searching for valuable markers including circulating endogenous metabolites associated with the risk of esophageal cancer, is extremely important A comparative metabolomics study was performed by using ultraperformance liquid chromatography-electrospray ionization-accurate mass time-of-flight mass spectrometry to analyze 53 pairs of plasma samples from ESCC patients and healthy controls recruited in Huaian, China. The result identified a metabolomic profiling of plasma including 25 upregulated metabolites and five downregulated metabolites, for early diagnosis of ESCC. With a database-based verification protocol, 11 molecules were identified, and six upregulated molecules of interest in ESCC were found to belong to phospholipids as follows: phosphatidylserine, phosphatidic acid, phosphatidyl choline, phosphatidylinositol, phosphatidyl ethanolamine, and sphinganine 1-phosphate. Clinical estimation of metabolic biomarkers through hierarchical cluster analysis in plasma samples from 17 ESCC patients and 29 healthy volunteers indicated that the present metabolite profile could distinguish ESCC patients from healthy individuals. The cluster of aberrant expression of these metabolites in ESCC indicates the critical role of phospholipid metabolism in the oncogenesis of ESCC and suggests its potential ability to assess the risk of ESCC development in addition to currently used risk factors. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs), 18-24 nt non-coding RNAs, are thought to play important roles in cell proliferation, differentiation, apoptosis, and development. Recent studies suggest that some of the known microRNAs map to a single genomic locale within a single polycistronic transcript. But the roles of the cluster remain to be known. In order to understand the role and mechanism of a cluster of miR-143 and miR-145 in esophageal squamous cell carcinoma (ESCC), the association of mature miR-143 and miR-145 expression with the risk for esophageal cancer was evaluated in ESCC patients with a case-control study, and target protein regulated by mature miRNA was analyzed in ESCC cell lines with 3'UTR luciferase reporter assay. The expression levels of miR-143 and miR-145 were determined in 110 pairs of esophageal cancer tissues and adjacent normal tissues using real-time reverse transcription PCR. The relative expression of miR-143 and miR-145 were statistically different between cancer tissues and matched controls. The combined expression of miR-143 and miR-145 was significantly associated with the risk for esophageal cancer. Meanwhile, the reduced expression of two miRNAs in tumor patient was supposed to have a trend of lymph node metastases. The co-expression pattern of miR-143 and miR-145 was analyzed with Pearson correlation. It showed a significant correlation between these two miRNAs expression both in tissues and tumor cell lines. 3'UTR luciferase reporter assay indicated that Fascin Homolog 1 (FSCN1) could be co-regulated by miR-143 and miR- 145. The protein level of FSCN1 showed no significant linear correlation with miR-143 and miR-145 expression in ESCC cell lines with Western blotting analysis. In conclusion, since miR-143 and miR-145 could regulate oncogenic FSCN1 and take part in the modulation of metastases, the result suggested the combination variable of miR-143 and miR-145 as a potential biomarker for earlier diagnosis and prognosis of esophageal cancer. [ABSTRACT FROM AUTHOR]

Prostate specific membrane antigen (PSMA) is overexpressed in prostatic adenocarcinoma (CaP), and its expression is negatively regulated by androgen stimulation. However, it is still unclear which factors are involved in this downregulation. TMPRSS2-ERG fusion is the most common known gene rearrangement in prostate carcinoma. Androgen stimulation can increase expression of the TMPRSS2-ERG fusion in fusion positive prostate cancer cells. The purpose of this investigation is to determine whether PSMA expression can be regulated by the TMPRSS2-ERG gene fusion. We employed two PSMA positive cell lines: VCaP cells, which harbor TMPRSS2-ERG fusion, and LNCaP cells, which lack the fusion. After 24 hours of androgen treatment, TMPRSS2-ERG mRNA level was increased in VCaP cells. PSMA mRNA level was dramatically decreased in VCaP cells, while it only has moderate change in LNCaP cells. Treatment with the androgen antagonist flutamide partially restored PSMA expression in androgen-treated VCaP cells. Knocking down ERG by siRNA in VCaP cells enhances PSMA expression both in the presence and absence of synthetic androgen R1881. Overexpressing TMPRSS2-ERG fusions in LNCaP cells downregulated PSMA both in the presence or absence of R1881, while overexpressing wild type ERG did not. Using PSMAbased luciferase reporter assays, we found TMPRSS2-ERG fusion can inhibit PSMA activity at the transcriptional level. Our data indicated that downregulation of PSMA in androgen-treated VCaP cells appears partially mediated by TMPRSS2-ERG gene fusion. [ABSTRACT FROM AUTHOR]

Carbon nanotubes have attracted attention not only due to electrical, optical, and mechanical applications but also due to their presence in biological and pharmaceutical products. In this study, modified multi-walled carbon nanotubes (MWCNT) were used as a model to evaluate potential subchronic effects of carbon nanotubes on mice. ICR mice were treated with phosphorylcholine-grafted multi-walled carbon nanotubes (MWCNT-PC) daily for 28 d at 10, 50, or 250 mg/kg by the intraperitoneal (ip) route. Subchronic exposure to MWCNT-PC did not produce any apparent systemic effects in mice. The body weight of the high-dose group was significantly lower than control in male mice, whereas tissue to body weight ratios of liver, spleen, and lung rose significantly with increase of dose of MWCNT-PC. There were significant differences between high-dose exposure and control groups. Accumulation of carbon nanotubes and inflammation response in liver, spleen, and lung were observed in the high-dose exposure group. No systemic toxicity and histopathological changes were found in 10-mg/kg exposure groups. Data in the present study support the view that MWCNT in vivo do not exert apparent marked effects in mice and that MWCNT products are relatively safe for human consumption. [ABSTRACT FROM AUTHOR]

Glutathione S-transferases (GST) belong to a superfamily of phase II enzymes believed to be associated with enhanced frequency of esophageal carcinoma. This study was performed to evaluate whether the GST family was associated with susceptibility to esophageal carcinoma in China. Ninety-seven patients with newly diagnosed, untreated esophageal squamous-cell carcinoma (ESCC) and 97 healthy controls matched in age, gender, and residence were recruited in this community-based case-control study. Null genotypes of GSTM1 and GSTT1 were determined by multiplex polymerase chain reaction (PCR) technique. Ile105Val polymorphism in the fifth exon, mRNA level, CpG island hypermethylation of promoter, and protein levels of GSTP1 gene were measured with peripheral blood mononuclear cell (PBMC) by PCR-restriction fragment length polymorphism (PCR-RFLP) techniques, quantitative real-time reverse transcription PCR, methylation-specific PCR (MSP), and Western blotting, respectively. The results showed that GSTM1 null genotype and GSTT1 null genotype were significantly associated with increased risk for esophageal cancer in Chinese population. Compared with the control, the relative expression levels of mRNA were significantly reduced in ESCC patients. The conditional logistic regression analysis demonstrated that increased risk for esophageal cancer was associated with CpG island hypermethylation of promoter of GSTP1 gene. GSTP1 protein levels also showed significant decrease in ESCC when adjusted for age, gender, smoking status, and alcohol use. An individual with GSTM1 or GSTT1 null genotype may thus be more susceptible to esophageal cancer development. Reduced expression in mRNA and protein levels were the main manifestations noted in aberrant function of GSTP1 gene. Data thus suggest that the CpG island hypermethylation of promoter gene may serve as a useful biomarker for early diagnosis of esophageal carcinoma development. [ABSTRACT FROM AUTHOR]

Single-nucleotide polymorphisms (SNP) in genes coding metabolizing enzymes modulate gene functions and cellular toxicity in response to chemicals. Quinone oxidoreductase 1 (NQO1) is an important detoxification enzyme involved in the catabolism of 1,4-benzoquinone (1,4-BQ), a benzene metabolite believed to be associated with bone-marrow toxicity and leukemia. Gene function was evaluated in immortalized human B lymphocytes derived from a Chinese Han population with independent genotypes at 2 NQO1 SNP sites. 1,4-Benzoquinone was incubated with these immortalized lymphocytes of differing genotypes. Among the genotypes of 2 SNP examined, cell lines with rs1800566CC showed a higher NQO1 enzymic activity after a 48 h of treatment with 10 μM 1,4-BQ, and a lower comet rate compared with cells of CT/TT genotypes. Data suggested that NQO1 rs1800566 might serve as a functional genetic marker for benzene toxicity in the Chinese Han population. The immortalized B lymphocytes derived from different populations might thus be used as a biomarker to detect functional genetic markers related to exposure to environmental chemicals. [ABSTRACT FROM AUTHOR]

As titanium dioxide (TiO2) nanoparticles are widely used commercially, the potential effects of TiO2 nanoparticles on humans are a concern. To evaluate the effects of TiO2 nanoparticles on hepatic and renal functions and correlate changes to oxidative stress, Sprague-Dawley rats were treated with TiO2 particles of two different specific surface areas (TiO2-S50: 50 m2/g, and TiO2-S210: 210 m2/g) at 0.5, 5, or 50 mg/kg body weight by intratracheal instillation. After 7 d, TiO2 nanoparticles produced no obvious acute toxicity on hepatic and renal functions. However, superoxide dismutase (SOD) activity of plasma and glutathione peroxidase (GSH-PX) activity of kidney in the low-dose TiO2-S210 group were significantly decreased. After TiO2-S210 exposure, malondialdehyde (MDA) levels of liver and kidney in intermediate and high-dose groups were significantly increased. This change only appeared in liver after TiO2-S50 exposure. Furthermore, SOD activity in liver and kidney and GSH-PX activity in kidney with low TiO2-S210 exposure group were significantly less than with low TiO2-S50. No apparent pathological changes in liver and kidney were observed. Intratracheal exposure to TiO2 nanoparticles may induce oxidative stress in liver and kidney, but does not influence hepatic or renal functions. There was no apparent evidence that TiO2-S210 was more toxic than TiO2-S50. In general, intratracheal exposure to TiO2 did not markedly affect extrapulmonary tissue functions. [ABSTRACT FROM AUTHOR]

Structural and functional changes ensue in cardiac cell networks when cells are guided by three-dimensional scaffold topography. We report enhanced synchronous pacemaking activity in association with slow diastolic rise in intracellular Ca2+ concentration ([Ca2+]i) in cell networks grown on microgrooved scaffolds. Topography-driven changes in cardiac electromechanics were characterized by the frequency dependence of Ca2+]i in syncytial structures formed of ventricular myocytes cultured on microgrooved elastic scaffolds (G). Cells were electrically paced at 0.5-5 Hz, and [Ca2+]i was determined using microscale ratiometric (fura 2) fluorescence. Compared with flat (F) controls, the G networks exhibited elevated diastolic [Ca2+]i at higher frequencies, increased systolic [Ca2+]i across the entire frequency range, and steeper restitution of Ca2+ transient half-width (n = 15 and 7 for G and F, respectively, P < 0.02). Significant differences in the frequency response of forcerelated parameters were also found, e.g., overall larger total area under the Ca2+ transients and faster adaptation of relaxation time to pacing rate (P < 0.02). Altered [Ca2+]i dynamics were paralleled by higher occurrence of spontaneous Ca2+ release and increased sarcoplasmic reticulum load (P < 0.02), indirectly assessed by caffeine-triggered release. Electromechanical instabilities, i.e., Ca2+ and voltage alternans, were more often observed in G samples. Taken together, these findings 1) represent some of the first functional electromechanical data for this in vitro system and 2) demonstrate direct influence of the microstructure on cardiac function and susceptibility to arrhythmias via Ca2+-dependent mechanisms. Overall, our results substantiate the idea of guiding cellular phenotype by cellular microenvironment, e.g., scaffold design in the context of tissue engineering. [ABSTRACT FROM AUTHOR]

A model-engineered cardiac construct is said to be having anisotropic properties and is also consisting of inter-connected cardiac cells with syncytial tissue-like behavior. Anisotropy is an essential feature of cardiac tissue. Previous attempts to mimic it in vitro have employed 2-D micropatterning, extracellular matrix manipulations or surface microabrasions. In contrast, this approach involved the introduction of a 3-D microenvironment and resulted in some interesting structural characteristics.