Polluting characteristics, sources, cancer risk, and cellular toxicity of PAHs bound in atmospheric particulates sampled from an economic transformation demonstration area of Dongguan in the Pearl River Delta, China.

The Songshan Lake Science and Technology Industrial Park is a national economic transition demonstration area, which centers at a traditional industrial region, in Dongguan, China. We were interested in the involved atmospheric particulates-bound PAHs regarding their sources, cancer risk, and related cellular toxicity for those in other areas under comparable conditions. In this study, the daily concentrations of TSP, PM10, and PM2.5 were averaged 127.95, 95.91, and 67.62 µg/m3, and the bound PAHs were averaged 1.31, 1.22, and 0.77 ng/m3 in summer and 12.72, 20.51 and 40.27 ng/m3 in winter, respectively. The dominant PAHs were those with 5-6 rings, and 4-6 rings in summer and winter, respectively. The incremental lifetime cancer risk (ILCR) (90th percentile probability) of total PAHs was above 1.00E-06 in each age group, particularly high in adolescents. Sensitivity analysis indicated that slope factor and body weight had greater impact than exposure duration and inhalation rate on the ILCR. Moreover, treatment of human bronchial epithelial BEAS-2B cells with mixed five indicative PAHs increased the formation of ROS, DNA damage (elevation in γ-H2AX), and protein levels of CAR, PXR, CYP1A1, 1A2, 1B1, while reduced the AhR protein, with the winter mixture more potent than summer. For the sources of PAHs, the stable carbon isotope ratio analysis and diagnostic ratios consistently pointed to petroleum and fossil fuel combustion as major sources. In conclusion, our findings suggest that particulates-bound PAHs deserve serious concerns for a cancer risk in such environment, and the development of new power sources for reducing fossil fuel combustion is highly encouraged.

Diversity and Co-Occurrence Patterns of Soil Bacterial and Fungal Communities of Chinese Cordyceps Habitats at Shergyla Mountain, Tibet: Implications for the Occurrence.

Chinese Cordyceps is a well-known medicinal larva-fungus symbiote distributed in the Qinghai-Tibetan Plateau and adjacent areas. Previous studies have involved its artificial cultivation but commercial cultivation is difficult to perform because the crucial factors triggering the occurrence of Chinese Cordyceps are not quite clear. The occurrence of Chinese Cordyceps is greatly affected by the soil environment, including the soil's physicochemical and microecological properties. In this study, the effects of these soil properties on the occurrence of Chinese Cordyceps were investigated. The results show that the physicochemical properties, including easily oxidizable organic carbon (EOC), soil organic carbon (SOC), humic acid carbon (HAC), humin carbon (HMC), and pH, might be negatively related to the occurrence of Chinese Cordyceps, and soil water content (SWC) might be positively related. Several soil physicochemical parameters (pH, SOC, HMC, HAC, available potassium (APO), available phosphorus (APH), microbial biomass carbon (MBC), and the ratio of NH4+ to NO3- (NH4+/NO3-)) and microbial properties interact and mix together, which might affect the occurrence of Chinese Cordyceps. Soil microbial community structure was also a possible factor, and a low level of bacterial and fungal diversity was suitable for the occurrence of Chinese Cordyceps. The intra-kingdom network revealed that a closer correlation of the bacterial community might help the occurrence of Chinese Cordyceps, while a closer correlation of the fungal community might suppress it. The inter-kingdom network revealed that the occurrence rate of Chinese Cordyceps might be negatively correlated with the stability of the correlation state of the soil habitat. In conclusion, this study shows that soil physicochemical properties and microbial communities could be greatly related with the occurrence of Chinese Cordyceps. In addition, soil physicochemical properties, the level of bacterial and fungal diversity, and correlations of bacterial and fungal communities should be controlled to a certain level to increase the production of Chinese Cordyceps in artificial cultivation.

miR-7-5p overexpression suppresses cell proliferation and promotes apoptosis through inhibiting the ability of DNA damage repair of PARP-1 and BRCA1 in TK6 cells exposed to hydroquinone.

Hydroquinone (HQ), one of the major metabolic products of benzene, is a carcinogen, which induces apoptosis and inhibit proliferation in lymphoma cells. microRNA-7-5p (miR-7-5p), a tumor suppressor, participates in various biological processes including cell proliferation and apoptosis regulation by repressing expression of specific oncogenic target genes. To explore whether miR-7-5p is involved in HQ-induced cell proliferation and apoptosis, we assessed the effect of miR-7-5p overexpression on induction of apoptosis analyzed by FACSCalibur flow cytometer in transfection of TK6 cells with miR-7-5p mimic (TK6- miR-7-5p). We observed an increased apoptosis by 25.43% and decreased proliferation by 28.30% in TK6-miR-7-5p cells compared to those negative control cells (TK6-shNC) in response to HQ treatment. Furthermore, HQ might active the apoptotic pathway via partly downregulation the expression of BRCA1 and PARP-1, followed by p53 activation, in TK6-miR-7-5p cells. In contrast, attenuated p53 and BRCA1 expression was observed in shPARP-1 cells than in NC cells after HQ treatment. Therefore, we conclude that HQ may activate apoptotic signals via inhibiting the tumor suppressive effects of miR-7-5p, which may be mediated partly by upregulating the expression of PARP-1 and BRCA1 in control cells. The increase of miR-7-5p expression further intensified downregulation of PARP-1 and BRCA1 in TK6-miR-7-5p cells, resulting in an increase of apoptosis and proliferation inhibited.

Bcl-2 protects TK6 cells against hydroquinone-induced apoptosis through PARP-1 cytoplasm translocation and stabilizing mitochondrial membrane potential.

B cell leukemia/lymphoma-2 (Bcl-2) suppresses apoptosis by binding the BH3 domain of proapoptotic factors and thereby regulating mitochondrial membrane potential (MMP). This study aimed to investigate the role of Bcl-2 in controlling the mitochondrial pathway of apoptosis during hydroquinone (HQ)-induced TK6 cytotoxicity. In this study, HQ, one metabolite of benzene, decreased the MMP in a concentration-dependent manner and induced the generation of reactive oxygen species (ROS), the activation of the DNA damage marker γ-H2AX, and production of the DNA damage-responsive enzyme poly(ADP-ribose)polymerase-1 (PARP-1). Exposure of TK6 cells to HQ leads to an increase in Bcl-2 and co-localization with PARP-1 in the cytoplasm. Inhibition of Bcl-2 using the BH3 mimetic, ABT-737, suppressed the PARP-1 nuclear to cytoplasm translocation and sensitized TK6 cells to HQ-induced apoptosis through depolarization of the MMP. Western blot analysis indicated that ABT-737 combined with HQ increased the levels of cleaved PARP and γ-H2AX, but significantly decreased the level of P53. Thus, ABT-737 can influence PARP-1 translocation and induce apoptosis via mitochondria-mediated apoptotic pathway, independently of P53. In addition, we found that knockdown of PARP-1 attenuated the HQ-induced production of cleaved PARP and P53. These results identify Bcl-2 as a protective mediator of HQ-induced apoptosis and show that upregulation of Bcl-2 helps to localize PARP-1 to the cytoplasm and stabilize MMP. Environ. Mol. Mutagen. 59:49-59, 2018. © 2017 Wiley Periodicals, Inc.

Differently expressed long noncoding RNAs and mRNAs in TK6 cells exposed to low dose hydroquinone.

Previous studies have shown that long noncoding RNAs (lncRNAs) were related to human carcinogenesis and might be designated as diagnosis and prognosis biomarkers. Hydroquinone (HQ), as one of the metabolites of benzene, was closely relevant to occupational benzene poisoning and occupational leukemia. Using high-throughput sequencing technology, we investigated differences in lncRNA and mRNA expression profiles between experimental group (HQ 20 µmol/L) and control group (PBS). Compared to control group, a total of 65 lncRNAs and 186 mRNAs were previously identified to be aberrantly expressed more than two fold change in experimental group. To validate the sequencing results, we selected 10 lncRNAs and 10 mRNAs for quantitative real-time PCR (qRT-PCR). Through GO annotation and KEGG pathway analysis, we obtained 3 mainly signaling pathways, including P53 signaling pathway, which plays an important role in tumorigenesis and progression. After that, 25 lncRNAs and 32 mRNAs formed the lncRNA-mRNA co-expression network were implemented to play biological functions of the dysregulated lncRNAs transcripts by regulating gene expression. The lncRNAs target genes prediction provided a new idea for the study of lncRNAs. Finally, we have another important discovery, which is screened out 11 new lncRNAs without annotated. All these results uncovered that lncRNA and mRNA expression profiles in TK6 cells exposed to low dose HQ were different from control group, helping to further study the toxicity mechanisms of HQ and providing a new direction for the therapy of leukemia.

Long non-coding RNAs: The novel diagnostic biomarkers for leukemia.

Long non-coding RNAs (LncRNAs) are a category of non-coding RNAs (ncRNAs) with a length of 200nt-100kb lacking a significant open reading frame. The study of lncRNAs is a newly established field, due in part to their capability to act as the novel biomarkers in disease. A growing body of research shows that lncRNAs may not only useful as biomarkers for the diagnosis and clinical typing and prognosis of cancers, but also as potential targets for novel therapies. Differential expression of lncRNAs has been found in leukemia in the last two years, however, the majority of the lncRNAs described here are transcripts of unknown function and their role in leukemogenesis is still unclear. Here, we summarize the lncRNAs associated with leukemia in order to find a potential classification tool for leukemia, and a new field of research is being explored.

LincRNa-p21: function and mechanism in cancer.

In view of the rapid development of gene chips and high-throughput sequencing technology, noncoding RNAs (ncRNas) form a high percentage of the mammalian genome. Two major subgroups of ncRNAs that have been identified are the long ncRNAs (lncRNas) and the microRNAs. A number of studies in the past few years have showed crucial functions for lncRNas in cancer. LincRNa-p21 as a p53-dependent transcriptional target gene and a potential diagnostic marker is involved in proliferation, cell cycle, metabolism and reprogramming. In addition, more researches revealed that lincRNa-p21 is associated with cancer progression and contributed to the treatment and prognosis of cancer. In this review, we briefly summarize the function and molecular mechanisms of lincRNa-p21 in cancer and its regulation for the genes expression .

Inhibition of autophagy enhances Hydroquinone-induced TK6 cell death.

Hydroquinone (HQ), one of the metabolic products of benzene, is a carcinogen. It can induce apoptosis in lymphoma cells. However, whether HQ can induce autophagy and what roles autophagy plays in TK6 cells exposured to HQ remains unclear. In this study, we found that HQ could induce autophagy through techniques of qRT-PCR, Western blot, immunofluorescent assay of LC3 and transmission electron microscope. Furthermore, inhibiting autophagy using 3-methyladenine (3-MA) or chloroquine (CQ) significantly enhanced HQ-induced cell apoptosis, suggesting that autophagy may be a survival mechanism. Our study also showed that HQ activated PARP-1. Moreover, knockdown of PARP-1 strongly exhibited decreased autophagy related genes expression. In contrast, the absence of SIRT1 increased that. Altogether, our data provided evidence that HQ induced autophagy in TK6 cells and autophagy protected TK6 from HQ attack-induced injury in vitro, and the autophagy was partially mediated via activation of the PARP-1-SIRT1 signaling pathway.

Cardiovascular disease in rheumatoid arthritis: medications and risk factors in China.

This study aims to assess the risk factors of cardiovascular disease (CVD) and to determine the association of traditional and biologic disease-modifying anti-rheumatic drugs (DMARDs) with risk for CVD in Chinese rheumatoid arthritis (RA) patients. A cross-sectional cohort of 2013 RA patients from 21 hospitals around China was established. Medical history of CVD was documented. The patients' social background, clinical manifestations, comorbidities, and medications were also collected. Of the 2013 patients, 256 had CVD with an incidence of 12.7%. Compared with non-CVD controls, RA patients with CVD had a significantly advanced age, long-standing median disease duration, more often male and more deformity joints. Patients with CVD also had higher rates of smoking, rheumatoid nodules, interstitial lung disease, and anemia. The prevalence of comorbidities, including hypothyroidism, diabetes mellitus (DM), hypertension, and hyperlipidemia, was also significant higher in the CVD group. In contrast, patients treated with methotrexate, hydroxychloroquine (HCQ), and TNF blockers had lower incidence of CVD. The multivariate analysis showed that the use of HCQ was a protective factor of CVD, while hypertension, hyperlipidemia, and interstitial lung disease were independent risk factors of CVD. Our study shows that the independent risk factors of CVD include hypertension, hyperlipidemia, and interstitial lung disease. HCQ reduces the risk of CVD in patients with RA.

Remission of rheumatoid arthritis and potential determinants: a national multi-center cross-sectional survey.

The aim of this study is to investigate the remission rate of rheumatoid arthritis (RA) in China and identify its potential determinants. A multi-center cross-sectional study was conducted from July 2009 to January 2012. Data were collected by face-to-face interviews of the rheumatology outpatients in 28 tertiary hospitals in China. The remission rates were calculated in 486 RA patients according to different definitions of remission: the Disease Activity Score in 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), the Clinical Disease Activity Index (CDAI), and the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean definition. Potential determinants of RA remission were assessed by univariate and multivariate analyses. The remission rates of RA from this multi-center cohort were 8.6% (DAS28), 8.4% (SDAI), 8.2% (CDAI), and 6.8% (Boolean), respectively. Favorable factors associated with remission were: low Health Assessment Questionnaire (HAQ) score, absence of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP), and treatment of methotrexate (MTX) and hydroxychloroquine (HCQ). Younger age was also predictive for the DAS28 and the Boolean remission. Multivariate analyses revealed a low HAQ score, the absence of anti-CCP, and the treatment with HCQ as independent determinants of remission. The clinical remission rate of RA patients was low in China. A low HAQ score, the absence of anti-CCP, and HCQ were significant independent determinants for RA remission.

In vitro susceptibility of Escherichia coli strains isolated from urine samples obtained in mainland China to fosfomycin trometamol and other antibiotics: a 9-year surveillance study (2004-2012).

BACKGROUND: As a result of extensive use of fluroquinlones and cephalosporins, urinary tract pathogens producing extended-spectrum beta-lactamase (ESBL) pose a considerable clinical challenge in the treatment of UTIs. In the present study we retrospectively assessed the susceptibility of E. coli strains to fosfomycin trometamol and other antibiotics commonly used for the treatment of such infections. METHODS: A total of 908 nonreplicate clinical E. coli urinary isolates were collected from 20 Chinese hospitals over four consecutive 1-year periods between October 2004 and June 2012. Susceptibility to antimicrobial agents fosfomycin trometamol, piperacillin-tazobactam, cefuroxime, cefotaxime, cefepime, imipenem, amikacin, levofloxacin, and nitrofurantoin was determined using the agar dilution method. A reference strain E. coli (ATCC 25922) was used as a positive control. Results were analyzed using Chi-square test or Fisher's exact tests. RESULTS: Fosfomycin trometamol, piperacillin-tazobactam, amikacin, and imipenem were consistently the most active agents against most of the isolates. There was a decline in susceptibility to cefuroxime, cefotaxime, and cefepime between 2004 and 2010. We showed that 528 of the 908 E. coli isolates (58.1%) produced ESBLs. The ESBL-positive rates increased from 41.7% in 2004-2005 to 60.9% in 2011-2012. ESBL-producing E. coli isolates showed significantly higher resistance rates to levofloxacin than the ESBL-negative isolates. Fosfomycin trometamol, piperacillin-tazobactam, amikacin, and imipenem had good activity against both levofloxacin-susceptible and levofloxacin- nonsusceptible isolates (sensitivity rate > 90%). However susceptibility of levofloxacin-resistant isolates to cefuroxime, cefotaxime, cefepime, amikacin, and nitrofurantoin was significantly lower than that of levofloxacin-susceptible isolates. CONCLUSIONS: Owing to the increase in the bacterial resistance across the world, the European Urology Association has recommended fosfomycin trometamol as the drug of choice in its Guidelines on Urological Infections released in 2013. Our results confirm this recommendation for use in China and continued monitoring of the susceptibility of E. coli to fosfomycin trometamol is need with the widely use of the drug in China.

Societal costs of rheumatoid arthritis in China: a hospital-based cross-sectional study.

OBJECTIVE: To estimate the annual direct and indirect costs of rheumatoid arthritis (RA) in China and identify the predictors for cost of illness. METHODS: A cross-sectional study of cost of illness from the societal perspective was conducted on 829 patients with RA in 21 tertiary care hospitals in China between July 2009 and December 2010. Data on demographics, clinical variables, and components of costs were collected by physician interview. Costs were represented in 2009 US dollars using purchasing power parity estimates. Univariate and multivariate linear regression analyses were performed to identify the predictors for cost of illness. RESULTS: The mean ± SD total cost of RA in China was $3,826 ± $5,659 per patient-year, given a gross domestic product per capita of $6,798 in China in 2009. Direct costs and indirect costs comprised 90.0% and 10.0% of the total costs, respectively. Drug expense represented approximately half of the total costs, dominated by biologic agents (48.2%) and disease-modifying antirheumatic drugs (23.5%). Additionally, the cost of extracted herbal drugs and traditional Chinese medicine comprised ∼17.6% of the drug expense. Higher education level, noninsured status, longer disease duration, more extraarticular manifestations, and higher Health Assessment Questionnaire score independently predicted higher total costs. CONCLUSION: Our results provide the first study of costs of RA in China. This study not only demonstrates the economic burden of RA, but also identifies the predictors that could be interventional factors to reduce the societal costs of RA in China.

HLA-DRB1 shared epitope-dependent DR-DQ haplotypes are associated with both anti-CCP-positive and -negative rheumatoid arthritis in Chinese Han.

The association between Human Leukocyte Antigen (HLA) class II and rheumatoid arthritis (RA) has been extensively studied, but few reported DR-DQ haplotype. Here we investigated the association of HLA-DRB1, DQA1, DQB1, and DR-DQ haplotypes with RA susceptibility and with anti-CCP antibodies in 281 RA patients and 297 control in Han population. High-resolution genotyping were performed. The HLA-DRB1 shared epitope (SE)-encoding allele *0405 displayed the most significant RA association (P = 1.35×10(-6)). The grouped DRB1 SE alleles showed great association with RA (P = 3.88×10(-13)). The DRB1 DRRAA alleles displayed significant protective effects (P = 0.021). The SE-dependent DR-DQ haplotype SE-DQ3/4/5 remained strong association with both anti-CCP -positive (P = 3.71×10(-13)) and -negative RA (P = 3.89×10(-5)). Our study revealed that SE alleles and its haplotypes SE-DQ3/4/5 were highly associated with RA susceptibility in Han population. The SE-DQ3/4/5 haplotypes were associated with both anti-CCP positive RA and -negative RA.

[Role of anti c-mpl antibody in systemic lupus erythematosus with thrombocytopenia].

OBJECTIVE: To determine whether anti-thrompoietin receptor (TPO-R, c-mpl) antibody contributes to thrombocytopenia in systemic lupus erytematosus (SLE) and explore the pathogenic role of this antibody. METHODS: Sera from 24 SLE patients with thrombocytopenia, 27 SLE patients having normal platelet counts with a history of thrombocytopenia, 18 SLE patients with neither thrombocytopenia nor post thrombocytopenia and 18 healthy controls were collected. Anti c-mpl antibodies were detected by an indirected ELISA assay. The serum TPO levels were measured by an ELISA assay. Clinical findings, autoantibody profiles, and SLEDAI were evaluated. RESULTS: Serum anti c-mpl antibodies were detected in 18.8% of the SLE patientis. The frequency of this antibody in SLE with thrombocytopenia, SLE with a history of thrombocytopenia and SLE without thrombocytopenia were of no difference (P=0.600). In the patients with anti c-mpl antibodies, their platelet counts were decreased(P=0.025) and serum TPO levels elevated(P=0.038) than those in the patients without, while there were no differences between the two groups in C3, C4, ESR, CRP level, the frequency of ANA, dsDNA, ANCA and SLEDAI. CONCLUSION: Anti c-mpl antibody contributes to SLE-associated thrombocytopenia by functionally blocking an interaction between thrombopoietin and c-mpl, which might inhibit TPO-dependent megakaryocyte proliferation and differentiation.

[Immunological characteristics of 1291 cases of severe acute respiratory syndrome in Beijing].

OBJECTIVE: To investigate the immunological characteristics of the cases of severe acute respiratory syndrome (SARS) in Beijing City. METHODS: Clinical data of 1291 patients with SARS from March to July 2003 in Beijing City were retrospectively analyzed. RESULTS: In patients with SARS, the absolute numbers of white blood cells, lymphocytes and CD(3), CD(4) and CD(8) lymphocyte subsets decreased during the early period of the disease, being manifested in 56.91%, 88.26%, 47.96%, 45.56% and 41.10% of the patients, respectively. During the first 3 days the median numbers of CD(3), CD(4) and CD(8) were 425 x 10(6)/L, 223 x 10(6)/L, 170 x 10(6)/L, respectively, being the lowest values in the course of the disease. During the second week the corresponding numbers were 536 x 10(6)/L, 267 x 10(6)/L, 224 x 10(6)/L, respectively; they returned to normal by the fourth week (P < 0.05), showing a trend of gradual increase during the disease progression. Comparison of different time points of the same cases also showed that CD(3), CD(4) and CD(8) were lowest in the first 1 - 3 days. The median number of CD(3) was higher (954 x 10(6)/L) during week 3, and there was no significant difference among other 3 weeks (P > 0.05). In the early period of the disease the CRP increased but ESR, C(3) and C(4) were still in normal ranges. CONCLUSIONS: In the early period of SARS, the WBC, lymphocytes, CD(3), CD(4) and CD(8) lymphocyte subsets decreased remarkably, and they tended to increase as the disease progressed. Simultaneous decreases in CD(3), CD(4) and CD(8) during the first week is a characteristic immunological change, which may facilitate the early diagnosis of SARS.