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OBJECTIVES: Serum CA72-4 levels are elevated in some gout patients but this has not been comprehensively described. The present study profiled serum CA72-4 expression in gout patients and verified the hypothesis that CA72-4 is a predictor of future flares in a prospective gout cohort. METHODS: To profile CA72-4 expression, a cross-sectional study was conducted in subjects with gouty arthritis, asymptomatic hyperuricaemia, four major arthritis types (OA, RA, SpA, septic arthritis) and healthy controls. A prospective gout cohort study was initiated to test the value of CA72-4 for predicting gout flares. During a 6-month follow-up, gout flares, CA72-4 levels and other gout-related clinical variables were observed at 1, 3 and 6 months. RESULTS: CA72-4 was highly expressed in patients with gouty arthritis [median (interquartile range) 4.55 (1.56, 32.64) U/ml] compared with hyperuricaemia patients [1.47 (0.87, 3.29) U/ml], healthy subjects [1.59 (0.99, 3.39) U/ml] and other arthritis patients [septic arthritis, 1.38 (0.99, 2.66) U/ml; RA, 1.58 (0.95, 3.37) U/ml; SpA, 1.56 (0.98, 2.85) U/ml; OA, 1.54 (0.94, 3.34) U/ml; P < 0.001, respectively]. Gout patients with frequent flares (twice or more in the last year) had higher CA72-4 levels than patients with fewer flares (fewer than twice in the last year). High CA72-4 level (>6.9 U/ml) was the strongest predictor of gout flares (hazard ratio = 3.889). Prophylactic colchicine was effective, especially for patients with high CA72-4 levels (P = 0.014). CONCLUSION: CA72-4 levels were upregulated in gout patients who experienced frequent flares and CA72-4 was a useful biomarker to predict future flares.
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Antígenos de Carbohidratos Asociados a Tumores/sangre , Artritis Gotosa/sangre , Brote de los Síntomas , Artritis Infecciosa/sangre , Artritis Reumatoide/sangre , Biomarcadores/sangre , Estudios Transversales , Femenino , Gota/sangre , Humanos , Hiperuricemia/sangre , Masculino , Persona de Mediana Edad , Osteoartritis/sangre , Estudios Prospectivos , Espondiloartritis/sangre , Factores de TiempoRESUMEN
Menin is a tumor suppressor encoded by the MEN1 gene that is mutated in patients with an inherited syndrome, multiple endocrine neoplasia type 1 (MEN1). Loss of menin has potent impact on proliferation of endocrine and non-endocrine cells. However, until recently little has been known as to how menin regulates cell proliferation. Rapid research progress in the past several years suggests that menin represses proliferation of endocrine cells yet promotes proliferation in certain types of leukemia cells via interacting with various transcriptional regulators. Menin interacts with histone H3 methyltransferases such as MLL (mixed lineage leukemia) protein. Increasing evidence has linked the biological function of menin to epigenetic histone modifications, control of the pattern of gene expression, and regulation of cell proliferation in a cell type-specific manner. In light of these recent findings, an emerging model suggests that menin is a crucial regulator of histone modifiers by acting as a scaffold protein to coordinate gene transcription and cell proliferation in a cell context-dependent manner. This recent progress unravels the coordinating role of menin in epigenetics and regulation of cell cycle, providing novel insights into understanding regulation of beta cell functions and diabetes, as well as the development and therapy of endocrine tumors and leukemia.
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Proliferación Celular , Proteína Metiltransferasas/fisiología , Proteínas Proto-Oncogénicas/fisiología , Genes Supresores de Tumor , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina , Humanos , Leucemia Bifenotípica Aguda/genética , Leucemia Bifenotípica Aguda/patología , Leucemia Bifenotípica Aguda/fisiopatología , Modelos Biológicos , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 1/patología , Neoplasia Endocrina Múltiple Tipo 1/fisiopatología , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/fisiología , Proteínas Proto-Oncogénicas/genética , Translocación GenéticaRESUMEN
OBJECTIVE: To compare the influence of percutaneous transforaminal endoscopic discectomy (PTED) and traditional operation on the nervous system function and the serum leu-enkephalin (LEK), glial fibrillary acidic protein (GFAP) and prostaglandin E-2 (PGE-2) in patients with senile lumbar spinal stenosis. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Department of Orthopedics Two, Xinjiang Changji Hui Autonomous Prefecture People's Hospital, Xinjiang, China, from March 2017 to March 2018. METHODOLOGY: A total of 146 patients with senile lumbar spinal stenosis were randomly divided into control group and observation group, 73 in each group. Control group underwent traditional operation, while the observation group underwent PTED. General situation of operation, serum LEK, GFAP, PGE-2, American Spinal Injury Association (ASIA) score and Japanese Orthopaedic Association (JOA) score were compared. RESULTS: Intraoperative blood loss in observation group was less than that in control group (p<0.001). Both operation time and length of hospital stay in observation group were shorter than those in control group (both p<0.001). At 24 hours later after operation, both levels of serum LEK and ASIA score in observation group were higher than those in control group (p=0.006 and p<0.001, respectively), and levels of serum GFAP and PGE-2 and JOA score in observation group were all lower than those in control group (all p<0.001). CONCLUSION: Compared with traditional operation, PTED has the advantages of less intraoperative blood loss, shorter operation time and length of hospital stay, etc. Besides, PTED can effectively reduce serum LEK, BFGF and PGE-2 expression in patients; and dramatically improve their nervous system function and lumbar function.
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Discectomía Percutánea/métodos , Endoscopía/métodos , Vértebras Lumbares/cirugía , Sistema Nervioso/fisiopatología , Estenosis Espinal/cirugía , Adulto , Pérdida de Sangre Quirúrgica , Encefalina Leucina/sangre , Femenino , Proteína Ácida Fibrilar de la Glía/sangre , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Fenómenos Fisiológicos del Sistema Nervioso , Tempo Operativo , Prostaglandinas E/sangre , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Growing very large size silicon ingots with low dislocation density is a critical issue for the photovoltaic industry to reduce the production cost of the high-efficiency solar cell for affordable green energy. The thermal stresses, which are produced as the result of the non-uniform temperature field, would generate dislocation in the ingot. This is a complicated thermal viscoplasticity process during the cooling process of crystal growth. A nonlinear three-dimensional transient formulation derived from the Hassen-Sumino model (HAS) was applied to predict the number of dislocation densities, which couples the macroscopic viscoplastic deformation with the microscopic dislocation dynamics. A typical cooling process during the growth of very large size (G5 size: 0.84 m × 0.84 m × 0.3 m) Si ingot is used as an example to validate the developed HAS model and the results are compared with those obtained from qualitatively critical resolved shear stress model (CRSS). The result demonstrates that this finite element model not only predicts a similar pattern of dislocation generation with the CRSS model but also anticipate the dislocation density quantity generated in the Si ingot. A modified cooling process is also employed to study the effect of the cooling process on the generation of the dislocation. It clearly shows that dislocation density is drastically decreased by modifying the cooling process. The results obtained from this model can provide valuable information for engineers to design a better cooling process for reducing the dislocation density produced in the Si ingot under the crystal growth process.
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Hyperuricemia (HU) is a cause of gout. Clinical studies show a link between HU and cardiovascular disease. However, the role of soluble serum urate (SU) on atherosclerosis development remains elusive. We aimed to use a new HU mouse model [Uricase/Uox knockout (KO)] to further investigate the relationship between HU and atherosclerosis. A mouse model by perivascular collar placement of induced carotid atherosclerosis was established in male Uox-KO mice. The Uox-KO mice had elevated SU levels and enhanced levels of atherosclerosis inflammatory response proteins. In contrast, Uox-KO mice with carotid atherosclerosis showed severe neointimal changes in histology staining consistent with increases in intimal area and increases in proliferating cell nuclear antigen (PCNA)- and F4/80-positive cells. Allopurinol reduced neointimal areas induced by the perivascular collar in hyperuricemic mice, accompanied by decreased expression of PCNA- and F4/80-positive cells. Urate-lowering treatment alleviated atherosclerosis inflammatory response factors and reactive oxygen species (ROS) intensities in both collar placement Uox-KO mice and urate-stimulated human umbilical vein endothelial cells (HUVECs). In vitro results using HUVECs showed ROS was induced by urate and ROS induction was abrogated using antioxidants. These data demonstrate that urate per se does not trigger atherosclerosis intima lesions in male mice. Urate worsens carotid neointimal lesions induced by the perivascular collar and urate-lowering therapy partially abrogates the effects. The current study warrants clinical studies on the possible benefits of urate-lowering therapy in atherosclerosis patients with HU.
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Alopurinol/farmacología , Enfermedades de las Arterias Carótidas/prevención & control , Hiperuricemia/complicaciones , Inflamación/prevención & control , Neointima/prevención & control , Urato Oxidasa/fisiología , Ácido Úrico/metabolismo , Animales , Antimetabolitos/farmacología , Enfermedades de las Arterias Carótidas/etiología , Enfermedades de las Arterias Carótidas/patología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Hiperuricemia/fisiopatología , Inflamación/etiología , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neointima/etiología , Neointima/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Low doses of febuxostat or benzbromarone are widely used in Asian countries, but lacking studies to compare the efficacy and safety of the two urate-lowering drugs. METHODS: To compare the efficacy and safety of low-dose febuxostat with low-dose benzbromarone in patients with primary gout, a randomized controlled, open-label trial was performed among male patients with primary gout for urate-lowering therapy (ULT) in a dedicated gout clinic in China. Randomization was carried out by a third-party institution according to random number table. Patients were randomly assigned 1:1 to febuxostat group (Feb group) (20 mg daily) or benzbromarone group (Ben group) (25 mg daily) and treated for 12 weeks. General information and biochemical data were collected at baseline and at every visit monthly. Clinical characteristics before and after the ULT were analyzed in the two groups by SPSS and EmpowerStats software. RESULTS: Two hundred forty patients were enrolled and randomized in the two groups, with 214 patients completing 12 weeks' ULT (105 in the Feb group and 109 in the Ben group). After 12 weeks, substantial percentages of patients in both Feb and Ben group achieved the target serum uric acid (sUA) (< 360 µmol/L) and serum urate levels were reduced significantly for both groups (Feb 39.5% and 156.83 µmol/L vs. Ben 35.7% and 163.99 µmol/L). Multivariate analysis suggests baseline sUA level and renal function were associated with the outcome of the rate of achieving target sUA (RAT). Sub-group analysis suggests low doses of febuxostat and benzbromarone rendered better RAT for patients with sUA < 540 µmol/L and creatinine clearance rate (Ccr) ≤ 110 mL min-1 1.73 m-2 at baseline. The drugs were well tolerated, and the incidence of gout flares in Feb group was similar with that in Ben group (22.85% vs. 33.94%). CONCLUSION: Overall, febuxostat 20 mg daily and benzbromarone 25 mg daily reduced sUA, and gout patients with sUA level < 540 µmol/L or Ccr ≤ 110 mL min-1 1.73 m-2 at baseline had better chance to achieve target uric acid levels. The current study suggests sUA level and renal function are key factors to consider when recommending low doses of febuxostat and benzbromarone to gout patients. TRIAL REGISTRATION: Registered with ChiCTR, No. ChiCTR1800019352 (retrospectively registered).
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Benzbromarona/administración & dosificación , Febuxostat/administración & dosificación , Tasa de Filtración Glomerular/fisiología , Gota/tratamiento farmacológico , Riñón/fisiopatología , Ácido Úrico/metabolismo , Biomarcadores/metabolismo , China , Relación Dosis-Respuesta a Droga , Estudios de Seguimiento , Gota/metabolismo , Gota/fisiopatología , Supresores de la Gota/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Uricosúricos/administración & dosificaciónRESUMEN
BACKGROUND: China approved adalimumab for the treatment of ankylosing spondylitis in 2013. However, the cost of the standard dose regimen exceeds ¥15â000 (around US$2250) per month, which is well beyond affordability for most Chinese patients. No biosimilars of adalimumab are available in China; IBI303 is a monoclonal antibody against TNFα that is currently in development. This study aimed to assess the clinical equivalence of IBI303 to adalimumab in patients with ankylosing spondylitis. METHODS: This phase 3, multicenter, double-blind, parallel, randomised controlled equivalence trial was done in 20 centers across China. Patients were randomly assigned in a 1:1 ratio to receive either 40 mg of IBI303 or 40 mg of adalimumab as a subcutaneous injection every 2 weeks until week 22. Patients were eligible for inclusion if they were between 18 and 65 years old, fulfilled the 1984 Modified New York Criteria for ankylosing spondylitis, were non-responders, inadequate responders, or intolerant to treatment with NSAIDs for 4 or more weeks, and had active ankylosing spondylitis defined by two or more indicators of disease severity. The investigators, site staff, patients, sponsors, and the contract research organisation were masked to treatment allocation. The primary outcome was the proportion of patients who met the Assessment of SpondyloArthritis international Society (ASAS) Response Criteria for a 20% improvement (ASAS20) at week 24 after treatment. Equivalence was established if the 95% CI of the difference in responses between groups was between -15% and 15%. Efficacy analyses were done in the full analysis population and in the per-protocol population. Safety analyses were done in all randomly assigned patients who received at least one drug dose. This trial is registered with ClinicalTrials.gov, number NCT02893254. FINDINGS: Between Sept 22, 2016, and May 11, 2018, 438 patients were randomly allocated either to the biosimilar IBI303 group (n=220) or the adalimumab group (n=218). In the full analysis population, 165 (75%) of 220 patients in the IBI303 group (95% CI 68·7-80·6) and 158 (72%) of 218 patients in the adalimumab group (66·0-78·3) reached the primary outcome of ASAS20 at week 24. The difference between the two groups was 2·3% with a 95% CI of -5·9 to 10·6, which fell within the pre-specified equivalence boundaries at week 24 (-15 to 15). In the per-protocol population, 163 (80%) of 203 patients in the IBI303 group reached ASAS20 at week 24 (95% CI 74·1-85·5), compared with 150 (80%) of 188 patients in the adalimumab group (73·3-85·3%). The difference between the groups was 0·6% with a 95% CI of -7·4 to 8·6%, which also fell within the pre-specified equivalence boundaries at week 24. Safety and tolerability profiles were similar between the two groups; 174 (79%) of 220 patients in the IBI303 group and 178 (82%) of 218 patients in the adalimumab group had treatment-emergent adverse events. INTERPRETATION: This trial showed therapeutic equivalence of IBI303 and adalimumab in the treatment of ankylosing spondylitis. The efficacy, safety, and immunogenicity of both drugs are highly similar. IBI303 could be an alternative treatment option for patients with ankylosing spondylitis in China. FUNDING: Innovent Biologics, National Major Scientific and Technological Special Project for "Significant New Drugs Development".
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The objective of this study is to analyze clinical characteristics associated with the formation of subcutaneous tophi among Chinese gout patients. It was a retrospective outpatient cohort study. Five thousand six hundred ninety-three gout patients treated at the Affiliated Hospital of Qingdao University from March 2011 to February 2016 were included and divided into the tophus group and non-tophus group according to the presence of megascopic tophus. Relevant clinical information and biochemical parameters were analyzed to identify potential risk factors for the incidence of subcutaneous tophi. There are significant difference (P < 0.05) between the tophus and non-tophus groups in gender, family history, exercise, incidence of obesity, hypertension, renal dysfunction, kidney stone, coronary heart disease, and upper limb joint involvement. Between the two groups, significant difference (P < 0.01) was detected in the onset age (43.80 ± 13.82 years vs. 45.40 ± 13.77 years), duration of disease (10.28 ± 7.54 years vs. 5.11 ± 6.06 years), number of joint involved (3.11 ± 2.15 vs. 1.81 ± 1.35), systolic pressure (138.53 ± 19.46 mmHg vs. 133.87 ± 17.93 mmHg), diastolic pressure (89.55 ± 12.73 mmHg vs. 87.48 ± 11.77 mmHg), serum uric acid (487.15 ± 120.13 µmol/L vs. 458.89 ± 119.04 µmol/L), creatinine (93.87 ± 54.19 µmol/L vs. 85.51 ± 37.71 µmol/L), and creatinine clearance rate (Ccr) (93.05 ± 48.7 mL/min vs. 106.61 ± 51.76 mL/min). Logistic regression analysis suggests that duration of disease, number of joints involved, involvement of upper limb joints, kidney stones, diastolic pressure, and serum uric acid are associated with the subcutaneous tophi formation, while exercise and obesity are protective factors. The present study has identified several clinical parameters (such as duration of disease, involvement of upper limb joints, involved joints, kidney stone, hypertension) as risk factors for the incidence of subcutaneous tophi, which provides insights into the treatment and prevention of tophus.
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Presión Sanguínea/fisiología , Gota/diagnóstico por imagen , Ácido Úrico/sangre , Adulto , Edad de Inicio , Anciano , China , Progresión de la Enfermedad , Femenino , Gota/sangre , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Vinclozolin, a widely used fungicide, can be identified as a residue in numerous vegetable and fruit samples. To get insight in its genetic toxicity, we investigated the genotoxic effect of vinclozolin in the human derived hepatoma cell line HepG2 using the micronucleus (MN) assay. Additionally, to evaluate the co- or anti-mutagenic potency of vinclozolin, we treated HepG2 cells with different concentrations of vinclozolin for 24 h. Subsequently, the cells were exposed to benzo[a]pyrene (BaP) for 1h. Exposure of HepG2 cells to 50-400 microM vinclozolin alone did not cause any induction of micronuclei. However, a pronounced co-mutagenic effect was observed. MN frequencies caused by BaP increased by 30.6%, 52.8% and 65.3% after pretreatment of the cell cultures with 50, 100 and 200 microM vinclozolin, respectively. The highest concentration (400 microM) of vinclozolin tested caused cytotoxicity. Therefore, micronuclei were not considered for that concentration. To clarify the mechanism of cogenotoxicity, we assayed cytochrome P450 1A1 (CYP1A1), which plays a pivotal role in activation of BaP. Cells exposed to vinclozolin led to significant increase of CYP1A1 expression in Western blot. The result suggested that induction of CYP1A1 by vinclozolin account for its enhancing effect on genotoxicity caused by BaP.
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Benzo(a)pireno/toxicidad , Fungicidas Industriales/toxicidad , Mutágenos/toxicidad , Oxazoles/toxicidad , Western Blotting , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citocromo P-450 CYP1A1/metabolismo , Humanos , Pruebas de MicronúcleosRESUMEN
Diallyl disulfide (DADS), an oil soluble constituent of garlic (Allium sativum), has been reported to cause antimutagentic and anticarcinogenic effects in vitro and in vivo by modulating phases I and II enzyme activities. In recent years, several studies suggested that the chemopreventive effects of DADS can also be attributed to induction of cell cycle arrest and apoptosis in cancer cells. In the present study, we reported that DADS-induced cell cycle arrest at G2/M and apoptosis in human A549 lung cancer cells in a time- and dose-dependent manner. Additionally, a significant increase of intracellular reactive oxygen species (ROS) was induced in A549 cells less than 0.5h after DADS treatment, indicating that ROS may be an early event in DADS-modulated apoptosis. Treatment of A549 cells with N-acetyl cysteine (NAC) completely abrogated DADS-induced cell cycle arrest and apoptosis. The result indicated that oxidative stress modulates cell proliferation and cell death induced by DADS.
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Compuestos Alílicos/farmacología , Antineoplásicos/farmacología , Carcinoma/patología , Ciclo Celular/efectos de los fármacos , Disulfuros/farmacología , Neoplasias Pulmonares/patología , Especies Reactivas de Oxígeno/metabolismo , Acetilcisteína/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Carcinoma/tratamiento farmacológico , Carcinoma/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Células Tumorales CultivadasRESUMEN
Chemoprevention is regarded as one of the most promising and realistic approaches in the prevention of human cancer. Among naturally occurring products, sulfur-containing compounds (OSCs), especially garlic compounds (GCs) and isothiocyanates (ITCs), represent two important and promising chemopreventive families because of their potent chemopreventive effects in various in vivo and in vitro models. In recent years, numerous investigations have shown that sulfur-containing compounds induce apoptosis in multiple cell lines and experimental animals. In the course of apoptosis induction by GCs and ITCs, multiple signal-transduction pathways and apoptosis intermediates are modulated. In particular, modulation of MAPKs and production of reactive oxygen species (ROS) seem to play pivotal roles in apoptosis induction by most GCs and ITCs. However, the role of P53 is still controversial. Based on present knowledge, GCs and ITCs may target not only the metabolism of carcinogens but also apoptosis signaling molecules. The effects of ITCs and GCs at multiple points of cancer development make these compounds highly promising candidates in cancer chemoprevention. However, the mechanisms of their anticancer effects are not fully understood, and further studies are required, especially to elucidate the role of cell-death receptors (the extrinsic pathway) and whether these agents induce apoptotic effects in non-tumor cells.
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Apoptosis/efectos de los fármacos , Compuestos de Azufre/farmacología , Ajo/química , Humanos , Isotiocianatos/farmacología , Células Tumorales CultivadasRESUMEN
Consumption of chlorinated drinking water is suspected to be associated with adverse health effects, including mutations and cancer. In the present study, the genotoxic potential of water from Donghu lake, Yangtze river and Hanjiang river in Wuhan, an 8-million metropolis in China, was investigated using HepG2 cells and the alkaline version of the comet assay. It could be shown that all water extracts caused dose-dependent DNA migration in concentrations corresponding to dried extracts of 0.167-167 ml chlorinated drinking water per ml medium. To explore whether the intracellular redox status is regulated by chlorinated drinking water, we determined lipid peroxidation (LPO) and depletion of reduced glutathione (GSH). The malondialdehyde (thiobarbituric acid (TBA)-reactive aldehydes) concentration increased after chlorinated drinking water treatment of HepG2 cells in a dose-dependent manner, the GSH content decreased. The activity of lactate dehydrogenase (LDH) increased in chlorinated drinking water treated HepG2 cells indicating cytotoxicity. In accordance with former studies which dealt with in vivo and in vitro micronucleus induction the present study shows that chlorinated drinking water from polluted raw water may entail genetic risks.
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Compuestos de Cloro/toxicidad , Daño del ADN , Abastecimiento de Agua , China , Ensayo Cometa , Desinfección , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Hepatoblastoma/patología , Humanos , L-Lactato Deshidrogenasa/metabolismo , Peroxidación de Lípido , Neoplasias Hepáticas/patología , Estrés Oxidativo , Medición de Riesgo , Ríos , Células Tumorales CultivadasRESUMEN
In this paper, we reviewed the data on the use of HepG2 cells to detect cytoprotective, antigenotoxic and cogenotoxic agents. Owing to their intact and inducible phase I and phase II enzymes, HepG2 cells are able to activate and detoxify xenobiotics and therefore reflect the metabolism of xenobiotics in the human body better than other metabolically incompetent cells used in conventional in vitro assays. Several dietary and non-dietary agents were found to be protective against different groups of cytotoxic and DNA-damaging xenobiotics in HepG2 cells and the mechanism of protection includes scavenging of electrophiles, reactive oxygen species and peroxides, inhibition of phase I activating enzymes, induction of phase II detoxifying enzymes and interactions with DNA-repair and/or replication processes. Additionally, certain non-mutagenic substances were found to enhance the effect of genotoxic agents in HepG2 cells by increasing the metabolic activation of the latter. In conclusion, HepG2 cells are of great relevance to detect cytotoxic and genotoxic substances and by extension cytoprotective, antigenotoxic and cogenotoxic agents.
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Ensayo Cometa/métodos , Citoprotección , Hígado/efectos de los fármacos , Pruebas de Micronúcleos/métodos , Xenobióticos , Línea Celular , Citoprotección/efectos de los fármacos , Citoprotección/genética , Citoprotección/fisiología , Humanos , Hígado/enzimología , Xenobióticos/antagonistas & inhibidores , Xenobióticos/toxicidadRESUMEN
Dong (D) lake and the Yangtze (Y) river are the main water supplies of the city of Wuhan, PR China. In the present study, the genotoxic effect of chlorinated drinking water (CDW) processed from raw water of D lake and Y river was evaluated in human HepG2 cells using the Comet assay and the micronucleus test. For that, HepG2 cells were exposed to XAD extracts of CDW corresponding to 0.167, 1.67, 16.7 and 167 ml CDW/ml cell culture. All CDW extracts caused a significant and dose-dependent increase of DNA migration in HepG2 cells. The level of DNA damage varied depending on the sampling time (season) and sampling site. The lowest concentration which caused a significant increase of DNA migration was 1.67 ml CDW/ml culture for water samples collected in August. Water samples collected in March showed their lowest observable effect levels in 167 ml and 16.7 ml CDW/ml culture for Y river and D lake, respectively. Additionally, significant increases of micronuclei (MN) frequencies were found in HepG2 cells after CDW treatment. However, in the MN assay the CDW samples collected in March exhibited higher genotoxicity than the August samples. In conclusion, HepG2 cells provide a useful tool for the detection of genotoxic effects of environmental mixtures.
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Ensayo Cometa/métodos , Daño del ADN , Hepatocitos/efectos de los fármacos , Hidrocarburos Clorados/toxicidad , Pruebas de Micronúcleos/métodos , Contaminantes Químicos del Agua/toxicidad , Abastecimiento de Agua , HumanosRESUMEN
Due to their bioaccumulation and their biological properties persistent organic pollutants (POPs) attract wide attention. In the present study we investigated the genotoxicity, cogenotoxicity and antigenotoxicity of three selected POPs (DDT, aroclor-1254 and toxaphene) in the HepG2 micronucleus assay. Exposure of HepG2 cells to DDT (17.8-60 microM) and aroclor-1254 (23-184 microM) alone did not increase the micronucleus-frequencies. A slight genotoxic effect could be observed after exposure to toxaphene (20-40 microM). Additionally, the ability of POPs to enhance/decrease the benzo(a)pyrene (BaP)-induced micronucleus formation was investigated. Exposure of HepG2 cells to 50 microM BaP alone led to a more than 2-fold increase of micronuclei (MN) compared with the background frequency. But when the cells were pretreated with 23-181 microM aroclor-1254 or 10-20 microM toxaphene, BaP exposure caused significantly more MN than BaP alone. In contrast, DDT (17.8-60 microM) reduced BaP-induced micronucleus induction by 6-38%. Mechanisms of action are discussed.
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Benzo(a)pireno/toxicidad , Contaminantes Ambientales/toxicidad , Hígado/metabolismo , Pruebas de Micronúcleos , Mutágenos/toxicidad , Compuestos Orgánicos/toxicidad , Línea Celular , DDT/toxicidad , Humanos , Indicadores y Reactivos , Insecticidas/toxicidad , Hígado/efectos de los fármacos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Toxafeno/toxicidadAsunto(s)
Gota , Reumatología , Alopurinol , Febuxostat , Supresores de la Gota , Humanos , United States Food and Drug AdministrationRESUMEN
Oncogenic fusion proteins are capable of initiating tumorigenesis, but the role of their wild-type counterparts in this process is poorly understood. The mixed lineage leukemia (MLL) gene undergoes chromosomal translocations, resulting in the formation of oncogenic MLL fusion proteins (MLL-FPs). Here, we show that menin recruits both wild-type MLL and oncogenic MLL-AF9 fusion protein to the loci of HOX genes to activate their transcription. Wild-type MLL not only catalyzes histone methylation at key target genes but also controls distinct MLL-AF9-induced histone methylation. Notably, the wild-type Mll allele is required for MLL-AF9-induced leukemogenesis and maintenance of MLL-AF9-transformed cells. These findings suggest an essential cooperation between an oncogene and its wild-type counterpart in MLL-AF9-induced leukemogenesis.
Asunto(s)
Regulación Leucémica de la Expresión Génica , Leucemia/genética , Proteína de la Leucemia Mieloide-Linfoide/fisiología , Proteínas de Fusión Oncogénica/fisiología , Alelos , Animales , Histonas/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Metilación , Ratones , Proteína de la Leucemia Mieloide-Linfoide/química , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/química , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas/metabolismo , Translocación GenéticaRESUMEN
DAS (diallyl sulfide), DADS (diallyl disulfide), and DATS (diallyl trisulfide) are major oil-soluble allyl sulfides (OAS) that represent major garlic constituents. The anticarcinogenic and antimutagenic effects of these substances have been extensively studied during the last decades. Previous reports suggest that induction of apoptosis by OASs might contribute to their chemopreventive effects. In this study, we report that OASs DADS and DATS induce significant apoptosis in human lung adenocarcinoma A549 cells, whereas DAS does not. Differential modulation of reactive oxygen intermediates (ROI) and mitochondria membrane potential (MMP) may account for the apoptotic effects of DADS and DATS. The underlying molecular mechanisms of apoptosis induction by both compounds include activation of C-Jun N-terminal kinase (JNK), up-regulation of p53, and down-regulation of bcl-2 expression. In our test series, up-regulation of extracellular signal-regulated protein kinase (ERK) was dispensable for apoptosis induction; DAS, DADS, or DATS did not modify expression of MAPK p38, bax, and bcl-xL. Further investigation revealed that the specific JNK inhibitor SP600125 and the antioxidant NAC blocked DADS and DATS-induced apoptosis, whereas ERK inhibitors did not. Additionally, our data provide the first evidence that Fas-mediated cell death pathway is partly involved in DADS but not DATS-mediated cell death. Taken together, our work has elucidated the triggers, important modulators, and signal transduction pathways in DADS and DATS-mediated apoptosis.
Asunto(s)
Compuestos Alílicos/farmacología , Anticarcinógenos/farmacología , Apoptosis/efectos de los fármacos , Aceites/química , Sulfuros/farmacología , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Compuestos Alílicos/química , Compuestos Alílicos/aislamiento & purificación , Anticarcinógenos/química , Anticarcinógenos/aislamiento & purificación , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Ciclina D1/metabolismo , Relación Dosis-Respuesta a Droga , Ajo/química , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Solubilidad , Sulfuros/química , Sulfuros/aislamiento & purificación , Proteína p53 Supresora de Tumor/metabolismo , Receptor fas/metabolismoRESUMEN
Oncogenic transformation usually leads to increase of cellular reactive oxygen species (ROS) level that renders the cells vulnerable to additional ROS production. By targeting ROS, a naturally occurring ROS-inducing compound, beta-phenylethyl isothiocyanate (PEITC), selectively kills the transformed cells but not normal cells.
Asunto(s)
Anticarcinógenos/farmacología , Apoptosis/efectos de los fármacos , Isotiocianatos/farmacología , Neoplasias/patología , Especies Reactivas de Oxígeno/metabolismo , Animales , Brassicaceae/química , Transformación Celular Neoplásica/efectos de los fármacos , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Neoplasias/metabolismo , Proteína Oncogénica p21(ras)/metabolismoRESUMEN
We studied the effects of sulfur-containing chemopreventive agents, including allyl sulfides and isothiocyanates, on human redox networks. Isothiocyanates inhibited isolated redox-active enzymes in a time- and dose-dependent manner. As shown for the most active compound, benzyl isothiocyanate (BITC), on thioredoxin reductase, the inhibition has an initial competitive part (Ki=6.1+/-1.0 microM) followed by a time-dependent irreversible inhibition (k2=72.8+/-25.5 M(-1) s(-1)). Also, glutathione reductase and glutathione S-transferase were irreversibly modified by BITC. Sulforaphane led to irreversible inhibition of the studied redox enzymes, but with 5-10 times lower k2 values. In contrast, allyl sulfides had only moderate effects on the tested enzymes. However, diallyl disulfide was found to react directly with reduced glutathione (k2=100 M(-2) s(-1)). This reaction might contribute to enhanced oxidative stress and the induction of the selenoprotein glutathione peroxidase as determined on activity and transcript levels. All chemopreventive agents tested induced transcript levels of genes associated with cell cycle arrest and apoptosis. This upregulation was accompanied by a dose-dependent decrease in cell number. Our data indicate that modulation of cellular redox networks is likely to contribute to the effects of sulfur-containing chemopreventive agents.