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1.
Ecotoxicol Environ Saf ; 207: 111562, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33254416

RESUMO

BACKGROUND: Low benzene exposure leads to hematotoxicity, but we still lack sensitive early monitoring and early warning markers. Benzene is associated with inflammation, which is mainly mediated by cytokines network. However, until now few studies have conducted high-throughput detection of multi-cytokines to get a global view of cytokine changes and screen for markers of benzene-induced toxicity. We hypothesized that cytokine profiles mediate benzene-induced hematotoxicity. METHODS: 228 subjects consisting of 114 low benzene exposed workers and 114 healthy controls were recruited at Research Center of Occupational Medicine, Peking University Third Hospital, Beijing. The serum concentrations of 27 cytokines were detected by cytokinomics array, urinary benzene series metabolites were measured by UPLC-MS/MS, and peripheral blood cell counts were observed by basic blood test. RESULTS: Among 27 cytokines, IL-9 and MIP1-α were significantly lower, but IL-4, IL-10, IL-15, MCP-1, TNF-α and VEGF were significantly higher in benzene exposure group than controls. Urinary benzene metabolite S-phenylmercapturic acid (S-PMA) was significantly higher in benzene exposure group and had a negative linear relationship with WBC count. S-PMA was only significantly associated with IL-9, meanwhile IL-9, IL-15 and VEGF had a positive linear relationship with WBC count. The bootstrapping mediation models showed that the effect of S-PMA on WBC count was partially explained by IL-9 for 10.11%. CONCLUSION: This study suggests that exposure to benzene was associated with alternation of blood cell count and cytokine profiles in workers exposed to low levels of benzene, especially decreases of WBC count and IL-9. We also found IL-9 partially mediated the effect of low benzene exposure on WBC count, which may be a potential and promising early monitoring and early warning marker of benzene hematotoxicity.


Assuntos
Poluentes Ocupacionais do Ar/metabolismo , Benzeno/metabolismo , Citocinas/sangue , Exposição Ocupacional/análise , Acetilcisteína/análogos & derivados , Adulto , Grupo com Ancestrais do Continente Asiático , Benzeno/análise , Biomarcadores/urina , Contagem de Células Sanguíneas , Cromatografia Líquida , Estudos Transversais , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/estatística & dados numéricos , Espectrometria de Massas em Tandem
2.
Toxicol Lett ; 332: 74-81, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32645459

RESUMO

Long-term exposure to benzene is associated with adverse health effects such as leukemia. Abnormal cell cycle progression has been reported participating in tumorigenesis. Our previous study found that lncRNA-OBFC2A was involved in benzene toxicity through regulating cell proliferation. However, the function of lncRNA-OBFC2A in the regulation of cell cycle remains obscure and the precise mechanisms need to be explored. In vitro study, results showed that benzene metabolic, 1,4-Benzoquinone (1,4-BQ), induced cell cycle arrest at the G1 phase accompanied with decreased expression of Cyclin D1 in a dose-dependently manner. Interestingly, lncRNA-OBFC2A overexpression was found in AHH-1 cells treated with 1,4-BQ and while interference with lncRNA-OBFC2A, the expression of Cyclin D1 were reversed. Further, we found that lncRNA-OBFC2A can interact with Smad3 to control cell cycle via modulating Cyclin D1 expression. In benzene exposed workers, the expression of lncRNA-OBFC2A and Smad3 increased while cyclin D1 decreased which was consistent with the in vitro experiment, meanwhile, the significant associations among them were also found. Thus, these findings indicate that lncRNA-OBFC2A targeted to Smad3 regulated cyclin D1 influences cell cycle arrest induced by 1,4-BQ. LncRNA-OBFC2A, Smad3 and Cyclin D1 as a set of biomarkers play important roles in benzene haematotoxicity.


Assuntos
Benzoquinonas/toxicidade , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ciclina D1/efeitos dos fármacos , RNA Longo não Codificante/efeitos dos fármacos , Proteína Smad3/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Fase G1/efeitos dos fármacos , Doenças Hematológicas/induzido quimicamente , Neoplasias Hematológicas/induzido quimicamente , Humanos , Proteômica
3.
Sci Total Environ ; 742: 140595, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-32629270

RESUMO

Our preliminary studies have suggested PFASs, heavy metals, and trace elements could bring significant risks to MetS. However, the role of epigenetic mechanisms (i.e., miRNAs) and risk factors of metabolic alternation (i.e., thyroid functions, glucose and lipids metabolism) are not fully understood. To test this hypothesis, a further cross-sectional study with 80 male MetS cases and 64 male references was undertaken. Negative association between the serum n-perfluorooctanoic acid (n-PFOA) with miR-140-5p was found [ß = -0.772; 95% confidence interval (CI), -0.244 to -0.300; p < 0.01, q < 0.05)] after adjusted with age. Higher levels of leptin and total bile acid were observed in the MetS group. The significantly positive associations between leptin with Cd (ß = 1.015, p < 0.01, q < 0.05), Cu (ß = 6.796, p < 0.05, q = 0.077) and Se (ß = 7.633, p < 0.05, q = 0.060) were found; whereas total bile acid was significantly associated with Se (ß = 8.954, p < 0.05, q = 0.140). Significantly positive associations between leptin and systolic/diastolic blood pressure were showed. Moreover, increased total bile acid concentrations were associated with hypertriglyceridemia [odds ratio (OR): 2.24 (95%CI, 1.10-4.58) adjusted by age.


Assuntos
Fluorcarbonetos , Síndrome Metabólica , Adulto , Pressão Sanguínea , Estudos Transversais , Humanos , Masculino , Fatores de Risco
4.
Nat Cell Biol ; 22(6): 630-639, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32367048

RESUMO

How transplanted haematopoietic stem cells (HSCs) behave soon after they reside in a preconditioned host has not been studied due to technical limitations. Here, using single-cell RNA sequencing, we first obtained the transcriptome-based classifications of 28 haematopoietic cell types. We then applied them in conjunction with functional assays to track the dynamic changes of immunophenotypically purified HSCs in irradiated recipients within the first week after transplantation. Based on our transcriptional classifications, most homed HSCs in bone marrow and spleen became multipotent progenitors and, occasionally, some HSCs gave rise to megakaryocytic-erythroid or myeloid precursors. Parallel in vitro and in vivo functional experiments supported the paradigm of robust differentiation without substantial HSC expansion during the first week. Therefore, this study uncovers the previously inaccessible kinetics and fate choices of transplanted HSCs in myeloablated recipients at early stage, with implications for clinical applications of HSCs and other stem cells.


Assuntos
Diferenciação Celular , Células Precursoras Eritroides/citologia , Células-Tronco Hematopoéticas/citologia , Megacariócitos/citologia , Células Mieloides/citologia , Análise de Célula Única/métodos , Transcriptoma , Animais , Ciclo Celular , Linhagem da Célula , Células Precursoras Eritroides/metabolismo , Feminino , Células-Tronco Hematopoéticas/metabolismo , Megacariócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo
5.
Cell Signal ; 72: 109622, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32240746

RESUMO

Increasing evidence suggests that circular RNAs are emerging biomarkers or targets for early cancer diagnosis and treatment. However, the studies of circular RNA in osteosarcoma (OS) are limited. In this study we found that circ_ARF3 were highly expressed in osteosarcoma cell lines and tumor tissues. Knocking down circ_ARF3 greatly ceased OS cell growth, impaired cell colony formation and halted cell cycle transition from G1 to S phase. Bioinformatic analysis suggested that miR-1299 is the target of circ_ARF3. Luciferase assay and biotin labeled circ_ARF3 pull down assay confirmed their interactions in OS cells. The regulatory roles of circ_ARF3 on miR-1299 was also investigated. Further bioinformatic analysis showed that CDK6 is the target of miR-1299. Overexpressing miR-1299 in OS cells decreased CDK6 expression and arrested OS cell growth and cell cycle progression. However, the roles of miR-1299 in regulating CDK6 expression, OS cell growth and cell cycle progression were greatly impaired in the presence of circ_ARF3. In general, our study demonstrated that in the OS, highly expressed circ_ARF3 acts as a sponge of miR-1299 to inhibit miR-1299 mediated CDK6 downregulation which further promoted OS pathogenesis. circ_ARF3 could be a potential target for OS treatment in the future.

6.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(1): 17-23, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31948519

RESUMO

OBJECTIVE: To study the value of body fat mass measured by bioelectrical impedance analysis (BIA) in predicting abnormal blood pressure and abnormal glucose metabolism in children. METHODS: Stratified cluster sampling was used to select the students aged 6-16 years, and a questionnaire survey and physical examination were performed. The BIA apparatus was used to measure body fat mass. Body mass index (BMI), body fat mass index (FMI), and fat mass percentage (FMP) were calculated. Fasting blood glucose level were measured. RESULTS: A total of 14 293 children were enrolled, among whom boys accounted for 49.89%. In boys and girls, the percentile values (P60, P65, P70, P75, P80, P85, P90, P95) of FMI and FMP fitted by the LMS method were taken as the cut-off values. Based on the receiver operating characteristic curve analysis, the P70 values with a better value in predicting abnormal blood pressure and blood glucose metabolism were selected as the cut-off values for excessive body fat. When FMI or FMP was controlled below P70, the incidence of abnormal blood pressure or abnormal glucose metabolism may be decreased in 8.25%-43.24% of the children. CONCLUSIONS: The evaluation of obesity based on FMI and FMP has a certain value in screening for hypertension and hyperglycemia in children, which can be further verified in the future prevention and treatment of obesity and related chronic diseases in children.


Assuntos
Tecido Adiposo , Adolescente , Pressão Sanguínea , Composição Corporal , Índice de Massa Corporal , Criança , Impedância Elétrica , Feminino , Glucose , Humanos , Masculino
7.
Artigo em Inglês | MEDLINE | ID: mdl-31843384

RESUMO

BACKGROUND: To our knowledge, we lack a complete understanding of the lipidomes alterations caused by maternal supraphysiological hypercholesterolemia (MSPH) at the third trimester. OBJECTIVES: The aim of this study was to investigate lipidomes alterations in maternal and umbilical venous (UV) serum and explore the association between these alterations and MSPH. METHODS: We conducted a nest case-control study between maternal physiological hypercholesterolemia (MPH) and MSPH subjects during pregnancy. Lipidomic profiling of maternal serum at the first trimester of gestation and UV serum was performed by ultra-high-performance liquid chromatography system connected to a quadrupole time-of-light/mass spectrometer. RESULTS: Several glycerophospholipids and sphingolipids (C18 sphingoid base) species were distinctly altered in maternal serum and/or UV serum with MSPH versus MPH. Glycerophospholipid metabolism, sphingolipid metabolism and propanoate metabolism were the main pathways that involved the most of discriminate metabolites. Higher HDL-c and phosphatidylcholine (16:0/0:0) (PC (16:0/0:0)) during pregnancy, higher PC (16:0/0:0) and lower cholesterol ester 20:4(8Z,11Z,14Z,17Z) (CE (20:4(8Z,11Z,14Z,17Z))) in the UV serum may be the risk factors for the increased placental circulation resistance. The total cholesterol levels of maternal serum both at the first trimester and at the third trimester were significantly correlated with some lipid species of UV serum. CONCLUSION: This study clarifies the differential lipid profiles to distinguish MSPH from MPH and the pathway which is influenced under the condition of MSPH. Also, it provides a resource to look for potential therapeutic targets for MSPH.


Assuntos
Hipercolesterolemia/sangue , Fosfatidilcolinas/sangue , Complicações na Gravidez/sangue , Esfingolipídeos/sangue , Adulto , Biomarcadores/sangue , Colesterol/sangue , Feminino , Sangue Fetal/metabolismo , Humanos , Hipercolesterolemia/prevenção & controle , Lipidômica , Espectrometria de Massas , Gravidez , Primeiro Trimestre da Gravidez/sangue
8.
Cell Death Dis ; 10(10): 772, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601785

RESUMO

Increasing evidence suggested that benzene exposure resulted in different types of hematological cancer. Both autophagy and apoptosis were reported to play vital roles in benzene toxicity, but the relationship between autophagy and apoptosis remain unclear in benzene-induced hematotoxicity. In this study, the toxic effect of benzene on autophagy and apoptosis in benzene-exposed workers and in vitro were verified. Results showed that benzene metabolite (1, 4-benzoquinone, 1, 4-BQ) dose-dependently induced autophagy and apoptosis via enhancing phosphorylation of Bcl-2 and beclin1. Finally, we also found that the elevated ROS was in line with enhancing the phosphorylation of Bcl-2 and beclin1 which contributed to 1, 4-BQ-induced autophagy and apoptosis. Taken together, this study for the first time found that the effect of 1, 4-BQ on the crosstalk between autophagy and apoptosis were modulated by the ROS generation via enhancing phosphorylation of Bcl-2(Ser70) and phosphorylation of beclin1(Thr119), which offered a novel insight into underlying molecular mechanisms of benzene-induced hematotoxicity, and specifically how the crosstalk between autophagy and apoptosis was involved in benzene toxicity. This work provided novel evidence for the toxic effects and risk assessment of benzene.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Benzeno/toxicidade , Benzoquinonas/urina , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Autofagossomos/efeitos dos fármacos , Autofagossomos/ultraestrutura , Proteína Beclina-1/química , Benzeno/metabolismo , Benzoquinonas/toxicidade , Humanos , Linfócitos/ultraestrutura , Microscopia Eletrônica de Transmissão , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/química , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/toxicidade
9.
EBioMedicine ; 47: 578-589, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31474553

RESUMO

BACKGROUND: Long term low-dose benzene exposure leads to the inhibition of haematopoiesis. However, the underlying mechanisms remained poorly defined, especially mediated by early effector molecules. METHODS: Here, we first found in mRNA microarray that pyroptotic classic genes (Casp1, 4, 5, and IL1ß) were up-regulated and represented dose-dependent differential expression in controls, low-dose benzene-exposed and chronic benzene-poisoned workers, and the expression of Casp1 and IL1ß were confirmed in low-dose benzene-exposed workers and was accompanied with elevated potent proinflammatory IL1ß. In vitro studies showed that benzene metabolites induced AHH-1 cell pyroptosis through activating Aim2/Casp1 pathway with the increased expression of GSDMD. Meanwhile, TET2 overexpression was elevated in vivo and in vitro and it was positively correlated with IL1ß. Further, we verified that pyroptosis caused by 1,4-BQ could be ameliorated in vitro by RNAi or pretreatment with Dimethyloxalylglycine (DMOG), the inhibitor of TET2. FINDINGS: Exposure to benzene can trigger pyroptosis via TET2 directly regulating the Aim2/Casp1 signaling pathway to cause haematotoxicity. INTERPRETATION: Benzene metabolites induced pyroptotic cell death through activation of the Aim2/Casp1 pathway which can be regulated by Tet2 overexpression. Tet2 may be a potential risk factor and is implicated in the development of benzene-related diseases. FUND: National Natural Science Foundation of China; the Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan; Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education.


Assuntos
Derivados de Benzeno/farmacologia , Caspase 1/metabolismo , Proteínas de Ligação a DNA/metabolismo , Hematopoese/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Piroptose/efeitos dos fármacos , Transdução de Sinais , Biomarcadores , Morte Celular , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Proteínas Proto-Oncogênicas/genética
10.
Ecotoxicol Environ Saf ; 185: 109672, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31541949

RESUMO

The potential toxicity of low-dose benzene exposure to human health has received attention, but the mechanisms of low-dose benzene-induced hematotoxicity remain largely unknown. The purpose of our study was to investigate the relationships between lncRNAVNN3 expression with benzene-induced autophagy and apoptosis in control and benzene-exposed workers. Seventy benzene-exposed workers and seventy non-benzene-exposed healthy workers were recruited. The expression of lncRNAVNN3, serum autophagy-associated and apoptosis-associated proteins were evaluated, and the relationship among them were also analysed. Furthermore, the mechanism of lncRNAVNN3 on autophagy and apoptosis induced by benzene metabolite (1, 4-benzoquinone, 1, 4-BQ) was investigated in vitro. The results showed that the expression of lncRNAVNN3 increased in benzene-exposed workers (p < 0.05). A positive correlation was found between lncRNAVNN3, serum autophagy-associated and apoptosis-associated proteins. In addition, we found that the knockdown of lncRNAVNN3 reduced phosphorylation of beclin1 and Bcl-2, which mediated 1, 4-benzoquinone-induced autophagy and apoptosis. Overall, lncRNAVNN3 mediated 1, 4-benzoquinone-induced autophagy and apoptosis though regulating phosphorylation of beclin1 and Bcl-2, suggesting that lncRNAVNN3 might be a novel early sensitive biomarker of benzene-induced hematotoxicity.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Amidoidrolases/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzeno/toxicidade , Moléculas de Adesão Celular/metabolismo , Exposição Ocupacional/efeitos adversos , RNA Longo não Codificante/metabolismo , Poluentes Ocupacionais do Ar/sangue , Poluentes Ocupacionais do Ar/urina , Proteína Beclina-1/sangue , Benzeno/metabolismo , Biomarcadores/sangue , Estudos de Casos e Controles , Linhagem Celular , Proteínas Ligadas por GPI/metabolismo , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/patologia , Exposição Ocupacional/análise , Proteínas Proto-Oncogênicas c-bcl-2/sangue
11.
Toxicol Appl Pharmacol ; 378: 114622, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31195003

RESUMO

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and occupational pollutants. To date, the effect and mechanism by which PAHs exposure impaired hematopoietic system remains unclear. METHODS: We examined the capability of PAHs to disrupt hematopoiesis in a study of 639 male participants in China by measuring complete blood counts (CBC) in 2013 and 2014. Gas chromatography-mass spectrometry (GC/MS) method was used to measure airborne levels of PAHs and benzene. We measured 1-hydroxypyrene (1-OHP), S-phenylmercapturic acid (SPMA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urinary by ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method. RESULTS: We found decreased dose-response of white blood cells, eosinophils, monocytes and lymphocytes with increased PAHs exposure in two consecutive years. We did not find association between benzene with CBC in our study. After stratification analysis by smoking status, the findings were highly consistent. White blood cells, monocytes and red blood cell counts were decreased in high urinary 8-OHdG group. CONCLUSIONS: Our study showed that PAHs could impair the hematopoietic system independently, and oxidative stress might play an important role in potential hematotoxicity.


Assuntos
Hematopoese/efeitos dos fármacos , Exposição Ocupacional/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , 8-Hidroxi-2'-Desoxiguanosina/efeitos adversos , Poluentes Ocupacionais do Ar/efeitos adversos , China , Cromatografia Líquida de Alta Pressão/métodos , Desoxiguanosina/efeitos adversos , Exposição Ambiental/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pirenos/efeitos adversos , Espectrometria de Massas em Tandem/métodos
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 950-957, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204960

RESUMO

OBJECTIVE: To observe the dynamic changes of hematopoietic reconstitution and multiple lineages differentiation at early phase after transplantation. METHODS: Whole bone marrow mononuclear cells (wBMMNC, 5×106) and enriched c-Kit+ hematopoietic stem/progenitor cells (HSPC, 3×105) from the BM of B6-Ly5.1 mice were transplanted into lethally irradiated B6-Ly5.2 mice, the frequencies and absolute numbers of donor-derived cells (including LKS- and LKS+) were detected by flow cytometry. The multiple lineages differentiation of donor-derived cells was also monitored by flow cytometry. The homing and early phase proliferations of donor-derived cells were observed by two-photon microscope. RESULTS: The donor-derived cells started to proliferation from 5-7 days after transplantation and reached the peak value at 2-3 weeks after wBMMNC transplantation. The donor-derived cells proliferated from 1-2 weeks and maintained until 4 weeks after c-kit+HSPC transplantation. At 1 week after transplantation, the donor-derived cells mainly differentiated into myeloid cells with a few lymphoid cells production (B cells) but the production of T cells was not observed at most in wBMMNC transplanted group, while myeloid cells occupied the majority of donor-derived cells at 2-4 weeks; donor-derived cells almost totally differentiated into myeloid cells at 1-3 weeks after transplantation in c-Kit+ transplanted group and donor-derived B cells appeared at 4 weeks. The absolute number of donor-derived LKS- and LKS+ cells in the BM of c-Kit+ transplanted group were much higher than that of wBMMNC group (P<0.001) at 2 weeks respectively. The clustering proliferation of cKit+ cells at 4-5 days after transplantation was observed by two photon microscope. CONCLUSION: The dynamical rate of proliferation and reconstitution of donor-derived cells are much earlier and quicker in c-Kit+ group than those of wBMMNC group. c-Kit+ cells mainly differentiate into myeloid cells within 1-3 weeks and the lymphoid cell differentiation starts at 4 weeks after transplantation. The immediate proliferation and differentiation of c-Kit+ cells within 1 week maybe due to the urgent needs of hematopoietic regeneration under the myeloablated hosts.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Animais , Transplante de Medula Óssea , Diferenciação Celular , Proliferação de Células , Camundongos , Camundongos Endogâmicos C57BL
13.
Onco Targets Ther ; 12: 2323-2333, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30992669

RESUMO

Aim: The aim of this study was to detect the effects and potential mechanisms of microRNA-221 on a series of biological behaviors of papillary thyroid carcinoma (PTC) cells in vitro and in vivo. Methods: First, we analyzed the relationship between the expression of miR-221 and several clinicopathological features of PTC patients and then detected the expression of the miR-221 in tumor tissues and cell lines. The effects of miR-221 on proliferation and invasion of PTC cells were verified by cell counting kit-8 (CCK-8) assay, wound healing assay and transwell assay. Western blot assay was applied to explore the correlation between miR-221 and RECK expression in PTC K1 cells. Finally, a xenograft model was established to further confirm the tumor-promoting effects of miR-221 in vivo. Results: Our data indicated that miR-221 was relatively upregulated in metastatic PTC tissues. MiR-221 promoted the proliferation, migration and invasion activities of PTC K1 cells, following variations of epithelial-mesenchymal transition (EMT)-related protein expression. We identified RECK as a direct target of miR-221, revealed its expression to be inversely correlated with miR-221 in PTC samples and showed that its reintroduction reverses miR-221-induced PTC invasiveness. In addition, miR-221 was also verified to promote tumor growth and increase tumor volume and weight in vivo. Taken together, miR-221/RECK axis could be an effective way to regulate biological behaviors of PTC. Conclusion: MiR-221 may be involved in PTC cell invasion and metastasis by targeting RECK, indicating that the miR-221/RECK pathway could be studied further as a potential new diagnostic or prognostic biomarker for PTC.

14.
Haematologica ; 104(10): 1950-1961, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30792200

RESUMO

Normal hematopoiesis can be disrupted by the leukemic bone marrow microenvironment, which leads to cytopenia-associated symptoms including anemia, hemorrhage and infection. Thrombocytopenia is a major and sometimes fatal complication in patients with acute leukemia. However, the mechanisms underlying defective thrombopoiesis in leukemia have not been fully elucidated. In the steady state, platelets are continuously produced by megakaryocytes. Using an MLL-AF9-induced acute myeloid leukemia mouse model, we demonstrated a preserved number and proportion of megakaryocyte-primed hematopoietic stem cell subsets, but weakened megakaryocytic differentiation via both canonical and non-canonical routes. This primarily accounted for the dramatic reduction of megakaryocytic progenitors observed in acute myeloid leukemia bone marrow and a severe disruption of the maturation of megakaryocytes. Additionally, we discovered overproduction of interleukin-4 from bone marrow endothelial cells in acute myeloid leukemia and observed inhibitory effects of interleukin-4 throughout the process of megakaryopoiesis in vivo Furthermore, we observed that inhibition of interleukin-4 in combination with induction chemotherapy not only promoted recovery of platelet counts, but also prolonged the duration of remission in our acute myeloid leukemia mouse model. Our study elucidates a new link between interleukin-4 signaling and defective megakaryopoiesis in acute myeloid leukemia bone marrow, thereby offering a potential therapeutic target in acute myeloid leukemia.


Assuntos
Células da Medula Óssea/metabolismo , Células Endoteliais/metabolismo , Interleucina-4/metabolismo , Leucemia Mieloide Aguda/metabolismo , Neoplasias Experimentais/metabolismo , Trombocitopenia/metabolismo , Animais , Células da Medula Óssea/patologia , Células Endoteliais/patologia , Interleucina-4/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Trombocitopenia/genética , Trombocitopenia/patologia
15.
Environ Pollut ; 248: 66-73, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30771749

RESUMO

Metabolic syndrome (MetS) is a global health problem with an increasing prevalence. However, effects of trace elements and heavy metals on MetS and the mechanism underlying this effect are poorly understood. A preliminary cross-sectional study was conducted in 2015. Significantly higher blood concentrations of lead (Pb), cadmium (Cd), copper (Cu), and selenium (Se) were observed in the MetS group. With a priori adjustment for age, the concentration of Cu and Se in the blood was associated with a 2.56 - fold [95% confidence interval (CI), 1.11, 5.92] and 3.31 - fold (95% CI, 1.4, 7.82) increased risk of MetS, respectively. Moreover, increased blood Se concentrations were associated with body mass index (BMI) [odds ratio (OR): 2.56; 95% CI, 1.11, 5.93], high blood pressure [for both systolic and diastolic blood pressures (SBP and DBP); OR: 3.82; 95% CI, 1.47, 7.31 for SBP and OR: 2.56; 95% CI, 1.18, 5.59 for DBP], and hypertriglyceridemia (OR: 3.3; 95% CI, 1.51, 7.2). In addition, the expression of miR-21-5p, miR-122-5p, and miR-146a-5p was significantly higher in subjects with MetS than those without MetS. Increased expression of miR-21-5p was significantly associated with increased SBP (ß = 5.28; 95% CI, 0.63, 9.94) and DBP (ß = 4.17; 95% CI, 0.68, 7.66). Moreover, Cu was positively associated with miR-21-5p (ß = 3.02; 95% CI, 0.07, 5.95), whereas Se was positively associated with miR-122-5p (ß = 2.7; 95% CI, 0.64, 4.76). The bootstrapping mediation models indicated that miR-21-5p partially mediated the relationships between Cu level and SBP/DBP. This study suggested that Cu and Se were both associated with MetS, and miR-21-5p participated in the development of MetS associated with Cu.


Assuntos
Síndrome Metabólica/sangue , Síndrome Metabólica/genética , Metais Pesados/sangue , MicroRNAs/genética , Oligoelementos/sangue , Adulto , Índice de Massa Corporal , Cádmio/sangue , China , Cobre/sangue , Estudos Transversais , Humanos , Hipertensão/sangue , Chumbo/sangue , Masculino , MicroRNAs/biossíntese , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Selênio/sangue
16.
Exp Hematol ; 60: 40-46.e2, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29307605

RESUMO

Impaired production of healthy hematopoietic cells from residual hematopoietic stem cells (HSCs) leads to high mortality in acute myeloid leukemia (AML). Previous studies have identified p21 and Egr3 as intrinsic factors responsible for the growth arrest and differentiation blockade of normal HSCs in leukemia; however, the related extrinsic factors remain unknown. In this study, we found that transforming growth factor ß (TGFß) signaling was upregulated in HSCs from bone marrow of mice with MLL-AF9-induced acute myeloid leukemia (AML) because of excessive production of TGFß1, especially from megakaryocytes, and overactivation of latent TGFß1 protein. We also found that SMAD3, a signal transducer of TGFß1, directly bound to Egr3 and upregulated its expression to arrest proliferation of HSCs. Our study provides evidence for targeting TGFß1 in AML to rectify normal hematopoiesis defects in clinical practice.


Assuntos
Proliferação de Células , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Megacariócitos/metabolismo , Proteínas de Neoplasias/biossíntese , Fator de Crescimento Transformador beta1/biossíntese , Animais , Células-Tronco Hematopoéticas/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Megacariócitos/patologia , Camundongos , Proteínas de Neoplasias/genética , Fator de Crescimento Transformador beta1/genética
17.
Environ Toxicol ; 33(2): 142-148, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29134718

RESUMO

Tertiary butyl alcohol (TBA) is a principal metabolite of methyl tertiary-butyl ether (MTBE), a common pollutant worldwide in the ground or underground water, which is found to produce nervous system damage. Nevertheless, few data regarding the effects of TBA has been reported. Studies indicated that oxidative stress plays a pivotal role in MTBE neurotoxic mechanism. Sirtuin 1 (SIRT1) has been reported to exert a neuroprotective effect on various neurologic diseases via resistance to oxidative stress by deacetylating its substrates. In this study, we examined levels of oxidative stress after exposure to TBA for 6 h in HT22 cells and HT22 cells with SIRT1 silencing (transfected with SIRT1 siRNA) or high expression (preconditioned with agonists SRT1720). We found that TBA activated oxidative stress by increasing generation of intracellular reactive oxygen species (ROS), malondialdehyde (MDA) and Oxidized glutathione (GSSG), and decreasing contents of superoxide dismutase (SOD) and glutathione reductase (GSH). In additional, levels of TBA-induced oxidative stress were aggravated when SIRT1 silenced but alleviated when SIRT1 enhanced. Our study indicated that SIRT1 mitigated oxidative stress induced by TBA.


Assuntos
Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/metabolismo , terc-Butil Álcool/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Redutase/metabolismo , Malondialdeído/metabolismo , Camundongos , Microscopia de Fluorescência , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Superóxido Dismutase/metabolismo
18.
Environ Pollut ; 233: 323-330, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29096305

RESUMO

Benzene is widely employed in the field of production, and its toxicity on biological systems has received increasing attention. Cell proliferation is a major life characteristic of living organisms. KLF15 and NOTCH1 are mature and classical genes in cell proliferation studies, particularly in the area of tumor investigation. The aim of this study was to investigate the effect and mechanism of VNN3 on cell proliferation induced by 1,4-benzoquinone (1,4-BQ), an important metabolite of benzene, and obtain a sensitive biomarker for the hazard screening and health care of benzene exposure. Normally growing AHH-1 cells were cultured in vitro and were incubated with different concentrations of 1,4-BQ (0, 10, 20, and 40 µM) for 24 h. A CCK-8 assay was used to assess the cell viability, whereas EdU was used to detect the cell proliferation of AHH-1 cells. The expression of VNN3, KLF15 and NOTCH1 was detected by real-time PCR. Moreover, a lentiviral model was constructed in AHH-1 cells to interfere with VNN3 expression. The results showed that 1,4-BQ clearly increased the expression of VNN3. Moreover, 1,4-BQ dose-dependently inhibited cell proliferation and caused increased KLF15 expression; in contrast, the NOTCH1 expression decreased in AHH-1 cells. Furthermore, following interference with the VNN3 expression, the cell proliferation inhibition and the expression of KLF15 and NOTCH1 were rescued. To further investigate the action of VNN3 in benzene hematotoxicity, we assessed it in benzene-exposed workers. The results showed that there was a remarkable correlation between the VNN3 expression and hemogram, which included RBC, NEUT and HGB. In addition, analysis of the KLF15 and NOTCH1 expression showed that the VNN3 expression was related to cell proliferation, which was consistent with the in vitro results. In conclusion, VNN3 influences cell proliferation induced by 1,4-BQ by regulating the expression of KLF15 and NOTCH1. VNN3 may represent a potential biomarker of benzene toxicity.


Assuntos
Benzeno/toxicidade , Benzoquinonas/toxicidade , Proliferação de Células/efeitos dos fármacos , Amidoidrolases/metabolismo , Biomarcadores/metabolismo , Moléculas de Adesão Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteínas Ligadas por GPI/metabolismo , Humanos , Reação em Cadeia da Polimerase em Tempo Real
19.
Chem Biol Interact ; 280: 45-50, 2018 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-29191453

RESUMO

Chemo-resistance is a serious obstacle for successful treatment of cancer. Apigenin, a dietary flavonoid, has been reported as an anticancer drug in various malignant cancers. This study aimed to investigate the potential chemo-sensitization effect of apigenin in doxorubicin-resistant hepatocellular carcinoma cell line BEL-7402/ADM. We observed that apigenin significantly enhanced doxorubicin sensitivity, induced miR-520b expression and inhibited ATG7-dependent autophagy in BEL-7402/ADM cells. In addition, we also showed that miR-520b mimics increased doxorubicin sensitivity and inhibited ATG7-dependent autophagy. Meanwhile, we indicated that ATG7 was a potential target of miR-520b. Furthermore, APG inhibited the growth of hepatocellar carcinoma xenografts in nude mice by up-regulating miR-520b and inhibiting ATG7. Our finding provides evidence that apigenin sensitizes BEL-7402/ADM cells to doxorubicin through miR-520b/ATG7 pathway, which furtherly supports apigenin as a potential chemo-sensitizer for hepatocellular carcinoma.


Assuntos
Apigenina/farmacologia , Proteína 7 Relacionada à Autofagia/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MicroRNAs/metabolismo , Animais , Antagomirs/metabolismo , Antagomirs/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apigenina/uso terapêutico , Autofagia/efeitos dos fármacos , Proteína 7 Relacionada à Autofagia/química , Proteína 7 Relacionada à Autofagia/genética , Sequência de Bases , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Doxorrubicina/toxicidade , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Alinhamento de Sequência , Transplante Heterólogo , Regulação para Cima/efeitos dos fármacos
20.
Sci Total Environ ; 621: 1542-1549, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29054655

RESUMO

As extensively used chemicals in a variety of consumer products, perfluoroalkyl substances (PFASs) are ubiquitous and could bring significant risk to human health. However, the effect of PFASs on metabolic syndrome (MetS) is not fully understood. In 2015, a preliminary cross-sectional study was undertaken. A total of 148 male subjects including 81 affected by MetS and 67 non-MetS participants as the reference were recruited from Physical Examination Center affiliated to Capital Medical University, China. Serum levels of perfluorohexane sulfonic acid (PFHxS), perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) were significantly higher in the subjects with MetS. Logistic regression results showed that concentration of PFNA in serum was associated with 10.9-fold [95% confidence interval (CI), 2.00-59.1] increased risk of MetS. Moreover, increased serum PFNA concentrations were associated with high blood pressure [both for systolic and diastolic blood pressure (SBP and DBP); odds ratio (OR) 7.52 (95%CI, 1.34-42.1) for SBP and 7.27 (95%CI, 1.17-45.1) for DBP], hypertriglyceridemia [13.2 (95%CI, 2.34-74.2)] and obesity [13.3 (95%CI, 2.38-74.4)], respectively. After adjustment by age in logistic regression models, serum levels of PFOA were associated with 29.4-fold (95%CI, 2.90-299.7) increased risk of MetS. Increased PFOA levels were also correlated with MetS [29.4 (95%CI, 2.9-299.7)], SBP [10.8 (95%CI, 1.31-90.0)], hypertriglyceridemia [16.6 (95%CI, 1.92-147.1)], and obesity [46.7 (95%CI, 4.47-487.7)] with adjustment for age. This study suggests bodily retention of PFASs and its association with MetS. Further clinical and animal studies are warranted to clarify the putative causal relationship.


Assuntos
Poluentes Ambientais/sangue , Fluorcarbonetos/sangue , Síndrome Metabólica/sangue , Adulto , China , Estudos Transversais , Humanos , Hipertensão/sangue , Hipertrigliceridemia/sangue , Masculino
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