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1.
Life Sci ; 251: 117607, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32240679

RESUMO

BACKGROUND: Arsenic trioxide (ATO) can bind directly to the human promyelocytic leukemia (PML) protein, leading to modification of PML by SUMOs. UBC9 is the only known E2-conjugating enzyme involved in SUMOylation. PML degradation via RNF4, an E3 ubiquitin ligases family member. PML is key organizer of nuclear bodies (NBs) that regulate many biological processes such as senescence, and DNA damage. ATO can activate the TGFß/Smad signaling pathway, causing liver fibrosis. However, the roles of PML Sumoylation in ATO-induced liver fibrosis remain unclear. OBJECTIVE: This study aimed to investigate the role of PML Sumoylation in the ATO-induced HSCs activation and to improve the mechanism of ATO-induced liver fibrosis. METHODS: Hepatic stellate cells (HSCs) were treated with 2 µmol/L ATO. Cell viability was detected by CCK-8 analysis. Immunoblot analysis and real-time quantitative PCR were used to detect the expression of IL-1ß, TNF-α, TGF-ß1, p-Smad2/3, α-SMA, Collagen I and PML SUMOylation after silencing PML, UBC9, and RNF4, respectively. The formation of PML-NBs was observed by immunofluorescence staining. RESULTS: 2 and 5 µmol/L ATO intervention increased HSCs cell viability. ATO was able to significantly trigger PML SUMOylation and the formation of PML-NBs. Inhibition of SUMOylated PML by silencing UBC9, subsequently preventing the downregulation of HSCs activation indicators induced by ATO (P < 0.05). Conversely, enhancing SUMOylated PML accumulation by silencing RNF4, activating TGFß/Smad signaling pathway, eventually promoting the induction of liver fibrosis. CONCLUSION: These results indicated that PML SUMOylation plays a critical role in the development of liver fibrosis induced by ATO.


Assuntos
Trióxido de Arsênio/toxicidade , Células Estreladas do Fígado/patologia , Cirrose Hepática/patologia , Proteína da Leucemia Promielocítica/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inativação Gênica , Humanos , Proteínas Nucleares/genética , Sumoilação , Fatores de Transcrição/genética , Enzimas de Conjugação de Ubiquitina/genética
2.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 37(1): 105-111, 2020 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-32096383

RESUMO

The article aims to explore the optimal concentration of arsenic trioxide (As 2O 3) on HepG2 of liver cancer cells, and the effect of As 2O 3 on the migration, invasion and apoptosis of HepG2 cells. In this study, the activity of HepG2 cells treated with 0, 1, 2, 4, 8, 16, 32 µmol/L As 2O 3 was tested by CCK-8 method, the semi-inhibitory concentration (IC50) was calculated, and the morphological changes of HepG2 cells were observed after the action of As 2O 3 at IC50 concentration for 12, 24, 48 h. The effect of As 2O 3 on cell migration and invasion ability was verified by wound healing experiment and Transwell invasion experiment. Western blot and qRT-PCR were used to detect the effects of As 2O 3 on the gene and protein expression levels related to cell migration, invasion and apoptosis. The results showed that, compared with the control group, the activity of HepG2 cells decreased with the increase of the concentration of As 2O 3 treatment, showing a dose-dependent effect, and its IC50 was 7.3 µmol/L. After 24 hours' treatment with 8 µmol/L As 2O 3, HepG2 cells underwent significant apoptosis, and its migration and invasion abilities were significantly reduced. In addition, the protein expression levels of RhoA, Cdc42, Rac1 and matrix metalloproteinase-9 (MMP-9) were down-regulated, the protein and mRNA expression levels of anti-apoptotic gene Bcl-2 were significantly down-regulated, and the protein and mRNA expression levels of pro-apoptotic genes Bax and Caspase-3 were significantly up-regulated. The above results indicate that certain concentration of As 2O 3 can inhibit the migration and invasion of hepatocellular carcinoma cells and promote the apoptosis of hepatocellular carcinoma cells.


Assuntos
Apoptose/efeitos dos fármacos , Trióxido de Arsênio/farmacologia , Carcinoma Hepatocelular/patologia , Movimento Celular/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Proliferação de Células , Células Hep G2 , Humanos , Invasividade Neoplásica
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 1-6, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027244

RESUMO

OBJECTIVE: To investigate the efficacy and safety of arsenic trioxide combined with ATRA and chemo- therapy for treatment of relapsed acute promyelocytic leukemia (APL) patients. METHODS: The clinic data of 25 patients with relapse APL treated in our hospital from 1996 to 2013 were collected and analyzed. Among the 25 patients, 15 patients suffered first-time hematological relapse (HR), and the other 10 patients showed first-time molecular relapse (MR). The patients with first-time replase were treated with ATO+ATRA+Anthracycline re-induction chemotherapy. The clinical features, complete remission (CR) rate, overall survival (OS), disease-free survival (DFS) and adverse events after re-induction therapy were analyzed. RESULTS: Fourteen of 15 hematological relapsed patients achieved the second-time hematological complete remission (CR2) after re-induction therapy except one patient died of bleeding complication during the re-induction. 8 of 14 patient showed molecular complete remission (CRm) after two cycles of therapy with this regimen. Totally, eleven out of the 14 HR patients were alive without disease till the last follow-up, and 3 of the 14 HR patients died because of bleeding complications. All of the 10 molecular relapsed patients received the second CRm after treated by the regimen. Among these 10 patients, 6 patients suffered only once relapse and continued with the molecular CR2 status, and for the other 4 patients with more than two-relapses, only 1 survived untill 89.3 months after achieved second-time CRm, and other 3 patients died because of bleeding complications. CONCLUSION: For relapsed APL patients, the treatment with ATO+ATRA+chemotherapy regimen after relapse still shows encouraging efficacy, no matter whether or not the application of ATO in the previous regimens. In addition, patients with more than two molecular relapses show a poor prognosis.


Assuntos
Arsenicais , Leucemia Promielocítica Aguda , Protocolos de Quimioterapia Combinada Antineoplásica , Trióxido de Arsênio , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Óxidos , Indução de Remissão , Resultado do Tratamento , Tretinoína
4.
Chemosphere ; 248: 126011, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32028161

RESUMO

The Giant Mine is an abandoned gold mine in Yellowknife, Northwest Territories, Canada. Throughout its operation from 1948 to 2004, the Giant Mine released heavy amounts of arsenic trioxide into the environment, thus contaminating the soil and surface water within and around the vicinity of the mine site. Chronic arsenic (As) poisoning negatively impacts wildlife health and can induce multi-organ damages including neurodegeneration and visual dysfunction depending on concentration and duration of exposure. The aim of the current study was to comparatively assess retina layer changes and prevalence of ocular lesions in wild rodent populations (i.e. muskrats and red squirrels) breeding in arsenic endemic areas of Yellowknife, near the vicinity of the abandoned Giant mine site (∼2 km radius), at an intermediate location (approximately 20 km from the mine area) as well as a reference location (spanning 52-105 km from the city of Yellowknife, Canada). Eye globes were removed from euthanized muskrats and squirrels from the three sampling locations with increasing distance from the Giant mine area. Optical Coherence Tomography (OCT) was used to attempt a pan-retinal layer assessment, and histologic examination was utilized for assessment and confirmation of ocular lesions. The retinal layers were measured and statistically compared between the groups based on sampling locations to enhance the scope of histologic evaluations. The preliminary results revealed that thicknesses of ganglion cell layer (GCL), retina nerve fibre layer (NFL), and inner retina layer (IR) were statistically reduced in the muskrats from arsenic endemic area, particularly near the vicinity of the Giant mine compared to the control group. Generalized ocular pathology was histologically confirmed in all the muskrats from the arsenic endemic areas with the manifestation of moderate to severe lymphocytic plasmacytic uveitis (LPU), keratitis and subcapsular cataracts. Inner retinal degeneration was also observed in all the muskrats from the arsenic endemic areas, while muskrats from the control group were predominantly normal. Three muskrats from the control group were noted to have a mild LPU and keratitis. Significant histopathologic changes were not detected in the squirrel eyes from the three groups except for incidental mild cornea scars from all the locations. In general, these preliminary findings confirm the presence of ocular lesions and retina abnormalities in wild muskrats in the Yellowknife area and provide the first evidence of visual dysfunction and impairment in wildlife inhabiting arsenic endemic areas of Canada.


Assuntos
Intoxicação por Arsênico/veterinária , Arsênico/toxicidade , Arvicolinae/metabolismo , Poluentes Ambientais/toxicidade , Sciuridae/metabolismo , Animais , Arsênico/análise , Arsênico/metabolismo , Trióxido de Arsênio , Cruzamento , Canadá , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/metabolismo , Ouro , Territórios do Noroeste , Solo
5.
Ecotoxicol Environ Saf ; 190: 110127, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31896471

RESUMO

The environmental hazards of arsenic (As) and copper (Cu) contamination have swept through quite a few districts worldwide. Whereas, molecular mechanisms involved in As- and Cu-induced immunotoxicity in Gallus gallus bursa of Fabricius (BF) are complex and elusive. Male Hy-line chickens were exposed to arsenic trioxide (As2O3; 30 mg/kg) and copper sulfate (CuSO4; 300 mg/kg) alone or in combination, respectively, to examine the potential ecotoxicity of them. The ions homeostasis and BF index of chicken had distinct changes after As or/and Cu exposure. Moreover, As or/and Cu treatment significantly increased the MDA content and NOS activity, and simultaneously resulted in reductions in CAT and AHR activities. Subsequently, it was further exhibited up-regulations of nuclear factor-κB (NF-κB), inflammatory mediators and pro-inflammation cytokines accompanied by depletion of anti-inflammatory cytokines and severe pathological conditions. Moreover, decreased ratio of IFN-γ/IL-4 and increased level of IL-17 illustrated an imbalance of the immune response. Meanwhile, incremental mRNA transcription and protein levels of heat shock proteins (HSPs) alleviated toxicity caused by As or/and Cu. Importantly, exposure to both contaminants significantly soared the BF injury in comparison with exposure to As or Cu alone. All these results illustrated that exposure to As2O3 or/and CuSO4 elicited BF tissue damage and ions changes, and its severity was associated with prolonged persistence of oxidative damage, accompanied by a dysregulated immune response which played a vital role in inflammatory injury. Additionally, combined management of As2O3 and CuSO4 could exacerbate BF injury.


Assuntos
Arsênico/toxicidade , Bolsa de Fabricius/fisiologia , Galinhas/fisiologia , Cobre/toxicidade , Estresse Oxidativo/imunologia , Animais , Trióxido de Arsênio , Bolsa de Fabricius/imunologia , Galinhas/metabolismo , Sulfato de Cobre/toxicidade , Citocinas/metabolismo , Proteínas de Choque Térmico/metabolismo , Inflamação/induzido quimicamente , Masculino , NF-kappa B/metabolismo
6.
J Cancer Res Clin Oncol ; 146(2): 485-492, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31686248

RESUMO

PURPOSE: Early death (ED) is the main cause of acute promyelocytic leukemia (APL) treatment failure, and the ED rate is higher for elderly patients than that for young ones. To date, no studies have been found focusing on ED in elderly patients with APL. METHODS: This study retrospectively analyzed the clinical data of 409 consecutive patients with APL (139 patients ≥ 50 years old, 270 patients < 50 years old). All patients received arsenic trioxide alone as induction therapy. The baseline clinical characteristics and ED occurrence and predictors between elderly and young patients with APL were compared and analyzed. RESULTS: The clinical features of elderly patients at admission were not significantly different from those of young ones. The ED rate of elderly patients was significantly greater than that of young patients (23.74% vs 11.85%, P = 0.0018). Hemorrhage is the main cause of ED in elderly patients, followed by infection and differentiation syndrome. From the 15th to 30th days of treatment, elderly patients had a higher mortality rate than that of young patients (7.83% vs 2.06%, P = 0.009). Male, white blood cell (WBC) count > 10 × 109/L, fibrinogen < 1.0 g/L and low albumin levels were independent risk factors for ED in elderly patients, while ED was only correlated with WBC count, fibrinogen and creatinine levels in young patients. CONCLUSION: The results of this study may help design more rational treatment plans for elderly patients with APL based on early mortality risk to reduce the ED rate.


Assuntos
Trióxido de Arsênio/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/mortalidade , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto Jovem
7.
Ecotoxicol Environ Saf ; 190: 110063, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31846860

RESUMO

Arsenic is a toxic metalloid that can cause male reproductive malfunctions and is widely distributed in the environment. The aim of this study was to investigate the cytotoxicity of arsenic trioxide (ATO) induced GC-1 spermatogonial (spg) cells. Our results found that ATO increased the levels of catalase (CAT) and malonaldehyde (MDA) and reactive oxygen species (ROS), while decreasing glutathione (GSH) and the total antioxidant capacity (T-AOC). Therefore, ATO triggered oxidative stress in GC-1 spg cells. In addition, ATO also caused severe mitochondrial dysfunction that included an increase in residual oxygen consumption (ROX), and decreased the routine respiration, maximal and ATP-linked respiration (ATP-L-R), as well as spare respiratory capacity (SRC), and respiratory control rate (RCR); ATO also damaged the mitochondrial structure, including mitochondrial cristae disordered and dissolved, mitochondrial vacuolar degeneration. Moreover, degradation of p62, LC3 conversion, increasing the number of acidic vesicle organelles (AVOs) and autophagosomes and autolysosomes are demonstrated that the cytotoxicity of ATO may be associated with autophagy. Meanwhile, the metabolomics analysis results showed that 20 metabolites (10 increased and 10 decreased) were significantly altered with the ATO exposure, suggesting that maybe there are the perturbations in amino acid metabolism, lipid metabolism, glycan biosynthesis and metabolism, metabolism of cofactors and vitamins. We concluded that ATO was toxic to GC-1 spg cells via inducing oxidative stress, mitochondrial dysfunction and autophagy as well as the disruption of normal metabolism. This study will aid our understanding of the mechanisms behind ATO-induced spermatogenic toxicity.


Assuntos
Trióxido de Arsênio/toxicidade , Autofagia/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espermatogônias/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Glutationa/metabolismo , Lisossomos/metabolismo , Masculino , Metabolômica , Camundongos , Mitocôndrias/ultraestrutura , Espécies Reativas de Oxigênio/metabolismo , Espermatogônias/enzimologia , Espermatogônias/metabolismo
8.
Environ Sci Pollut Res Int ; 26(36): 36343-36353, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31713821

RESUMO

Arsenic (As) and copper (Cu) are ubiquitous pollutants that pose a threat to the environment. Our aim is to study the underlying mechanisms by which As and Cu act on the chicken gizzard. In order to detect ionic disorders in chicken gizzard under chronic treatment with As3+ and/or Cu2+ and whether they can induce oxidative damage as well as immune disorders, 30 mg/kg arsenic trioxide (As2O3) and/or 300 mg/kg copper sulfate (CuSO4) were added to the chicken's basal diet. After 12 weeks of exposure, trace elements were found to have significant interference, accompanied by damage to the antioxidant system. In addition, As3+ and/or Cu2+ activated the nuclear factor kappa B (NF-κB), inducing severe inflammation. At the same time, damaged structural integrity which might be caused by inflammation was discovered after hematoxylin and eosin (H&E) staining. Moreover, symbolic Th1/Th2 (Th, helper T cell) drift was also observed in treatment groups, meaning that immune function is left to be affected, and the increment in heat shock proteins may be a self-protective mechanism of gizzard. Interestingly, we found that the damage to the gizzard of chicken was aggravated in a time-dependent manner, and the combined exposure was more pathogenic than the single exposure, of which the mechanism needs further exploration. Together, this work helps move us toward a better understanding of the molecular mechanisms that mediate the interactions between Cu excess and As3+ exposures and possible health consequences in susceptible species.


Assuntos
Trióxido de Arsênio/toxicidade , Galinhas , Sulfato de Cobre/toxicidade , Poluentes Ambientais/toxicidade , Moela das Aves/efeitos dos fármacos , Proteínas de Choque Térmico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Galinhas/imunologia , Galinhas/metabolismo , Moela das Aves/imunologia , Moela das Aves/metabolismo , Inflamação/metabolismo , Oligoelementos/metabolismo
9.
Zhonghua Nei Ke Za Zhi ; 58(12): 908-910, 2019 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-31775455

RESUMO

To retrospectively analyze the safety and efficacy of low dose subcutaneous decitabine combined with arsenic trioxide in patients with intermediate or high-risk myelodysplastic syndrome (MDS). Three of the total 11 MDS patients achieved complete remission (CR) and 6 achieved hematological improvement (HI), 1 stable disease (SD), and 1 progressive disease (PD). One patient was treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). The median follow-up time was 413(90-1 275) d. Nine patients were still alive. Low dose subcutaneous decitabine combined with arsenic trioxide can be an alternative regimen for intermediate or high-risk MDS patients.


Assuntos
Trióxido de Arsênio/uso terapêutico , Decitabina/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Trióxido de Arsênio/administração & dosagem , Decitabina/uso terapêutico , Humanos , Estudos Retrospectivos , Resultado do Tratamento
10.
Rinsho Ketsueki ; 60(10): 1431-1435, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31695003

RESUMO

We report a 55-year-old man who began undergoing hemodialysis for polycystic kidney disease 17 years ago. Because pancytopenia and susceptibility to infection were identified, a bone marrow biopsy was performed, resulting in a diagnosis of acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA) treatment was initiated, but promyelocytic leukemia/retinoic acid receptor alpha gene fusion without remission was identified by fluorescence in situ hybridization. We administered ATRA/arsenic trioxide (ATO) combination therapy for therapy-resistant APL and confirmed molecular genetic remission. The ATRA/ATO combination therapy was continued, obtaining complete remission 2 years after commencement of treatment. Cystic infections continued during ATRA/ATO combination therapy, similar to infections before APL morbidity, and there were no adverse events leading to treatment discontinuation. ATRA/ATO combination therapy is considered a safe and effective treatment for therapy-resistant APL patients on hemodialysis.


Assuntos
Trióxido de Arsênio/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Doenças Renais Policísticas , Indução de Remissão , Diálise Renal , Resultado do Tratamento
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1380-1386, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607287

RESUMO

OBJECTIVE: To investigate the effect of chromosomal karyotype on the prognosis of patients with acute promyelocytic leukemia (APL) in condition of the maintenance treatment based on arsenic trioxide. METHODS: The patients with acute promyelocytic leukemia for last 12 years in our hospital were retrospectively collected. The patients mainly treated with arsenic trioxide in maintenance protocol were selected and followed up. All the patients were divided into 3 groups according to cytogenetic data: single t (15; 17) group, t (15; 17) with additional chromosomal abnormality (ACA) group, and normal karyotype group. Then, the prognostic significance of ACAs and complex karyotype were investigated in APL patients. RESULTS: There were 57 cases in the single t (15; 17) group, in which 8 cases died in the first month after induction treatment with early mortality rate of 14%. There were 21 patients in t (15; 17) with ACA group, in which 4 cases died in the first month with early mortality rate of 19%. There were 15 cases in normal chromosome group, in which 5 cases died in the first month with the early mortality rate of 33.3%. There was no statistical difference in the early mortality among 3 groups. All the remaining 76 patients achieved complete hematological remission. These patients were followed up. The median follow-up time was 43.9 months. Among them, only 2 patients in single t (15; 17) group and 1 patient in t (15; 17) with ACA group relapsed. No patient relapsed in normal karyotype group. The relapse rate was 3.5% in single t (15; 17) group and 4.2% in t (15; 17) with ACA group, respectively. There was no statistical difference in the overall survival and disease-free survival rates among 3 groups. Further analysis showed that the patients with complex chromosome karyotypes had lower relapse-free survival rates, but overall survival rates were not significantly different in 3 group. CONCLUSION: In general, ACA can not affect the prognosis of patients with acute promyelocytic leukemia in condition of the maintenance treatment based on arsenic trioxide, but the complex chromosomal karyotype may reduce the relapse-free survival rates.


Assuntos
Trióxido de Arsênio/uso terapêutico , Leucemia Promielocítica Aguda , Humanos , Cariótipo , Leucemia Promielocítica Aguda/tratamento farmacológico , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Tretinoína
12.
Zhonghua Zhong Liu Za Zhi ; 41(9): 675-680, 2019 Sep 23.
Artigo em Chinês | MEDLINE | ID: mdl-31550857

RESUMO

Objective: To investigate the inhibitory effect of programmed cell death factor 4 (PDCD4) on arsenic trioxide (As(2)O(3))-induced cell growth and nuclear factor kappa B (NF-κB) signaling pathway in neuroblastoma. Methods: The PDCD4 overexpression vector was transfected into neuroblastoma cells and detected by fluorescence quantitative PCR and Western blot. As(2)O(3) was used to treat PDCD4 overexpressing neuroblastoma cells. MTT assay was used to measure the proliferation. Colony formation assay was used to determine the cell clone forming ability. Apoptosis was measured by flow cytometry. Western blot was used to detect the expression of NF-κB p65 and cleaved caspase-3 protein in cells. Results: The transfection of PDCD4 overexpression vector significantly increased the expression level of PDCD4 in neuroblastoma cells. The cell survival rates of the control group, PDCD4 group, As(2)O(3) group and As(2)O(3)+ PDCD4 group were 100%, (72.14±5.20)%, (62.58±3.14)% and (40.87±2.47)%, respectively. The colony formation rates in these four groups were (91.25±8.36)%, (65.32±7.14)%, (57.23±5.28)% and (37.14±3.64)%, respectively. In addition, the cell apoptotic rates of these four groups were (3.57±0.24)%, (28.64±3.20)%, (36.41±4.58)% and (49.65±5.27)%, respectively. Therefore, overexpression of PDCD4 in the absence or presence of As(2)O(3) inhibited cell proliferation and clone formation ability, while promoted apoptosis. Furthermore, the expression levels of cleaved caspase-3 in the control group, PDCD4 group, As(2)O(3) group and As(2)O(3)+ PDCD4 group were 0.21±0.03, 0.30±0.02, 0.43±0.05 and 0.57±0.06, respectively. And the expression levels of NF-κB p65 protein were 0.68±0.04, 0.52±0.03, 0.43±0.04, and 0.32±0.02, respectively. Compared with the control group, the expression levels of NF-κB p65 protein in PDCD4 group, As(2)O(3) group and As(2)O(3)+ PDCD4 group were significantly decreased (P<0.05), whereas the expression level of cleaved Caspase-3 protein was significantly increased (P<0.05). The changes in As(2)O(3)+ PDCD4 group were more significant than those in PDCD4 group and As(2)O(3) groups (both P<0.05). Conclusion: PDCD4 enhances the inhibitory effect of As(2)O(3) on the growth and NF-κB signaling pathway in neuroblastoma cells.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Apoptose/efeitos dos fármacos , Trióxido de Arsênio/farmacologia , NF-kappa B/fisiologia , Neuroblastoma/tratamento farmacológico , Proteínas de Ligação a RNA/genética , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos , Proteínas Reguladoras de Apoptose/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Proteínas de Ligação a RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
Ecotoxicol Environ Saf ; 185: 109678, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31557571

RESUMO

Arsenic and copper are naturally occurring element. Contamination from natural processes and anthropogenic activities can be discovered all over the world and their unique interactions with the environment lead to widespread toxicity. When the content was excessive, the organism would be hurt seriously. The glandular stomach is an important organ of the poultry gastrointestinal tract. This study was aimed to investigate the toxicity of arsenic trioxide or/and copper sulfate (As or/and Cu) on chicken glandular stomach. Seventy-two 1-day-old Hy-Line chickens were randomly divided into control (C) group, arsenic trioxide (As) group, copper sulfate (Cu) group and arsenic trioxide and copper sulfate (AsCu) group, and exposed to 30 mg/kg arsenic trioxide or/and 300 mg/kg copper sulphates for 12 weeks. The indicators of mitochondrial dynamics, apoptosis and autophagy were tested in the glandular stomach. The results showed that exposure to As or/and Cu caused mitochondrial dynamic imbalance. Additionally, the levels of pro-apoptosis and autophagy indicators were increased and the levels of anti-apoptosis indicators were decreased in the treatment groups. Beyond that, in the treatment groups, we could clearly see karyopyknosis and chromatin condensation were associated with increased apoptosis rate, as well as the disappearance of the nuclear membrane, the swelling of mitochondria and the accumulation of autophagosomes were involved in the death of cells. It was worth noting that the glandular stomach lesions were time-dependent, and the combination of As and Cu were worse than the As and Cu alone. Collectively, our results suggest that As or/and Cu aggravate mitochondrial dysfunction, apoptosis and autophagy in a time-dependent manner, and the combined toxicity of As and Cu was higher.


Assuntos
Apoptose/efeitos dos fármacos , Trióxido de Arsênio/toxicidade , Autofagia/efeitos dos fármacos , Galinhas , Sulfato de Cobre/toxicidade , Poluentes Ambientais/toxicidade , Dinâmica Mitocondrial/efeitos dos fármacos , Estômago/efeitos dos fármacos , Animais , Sinergismo Farmacológico , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Estômago/patologia
14.
Int J Mol Sci ; 20(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480400

RESUMO

The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood-brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonas/uso terapêutico , Adulto , Trióxido de Arsênio/farmacologia , Trióxido de Arsênio/uso terapêutico , Sequência de Bases , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Pré-Escolar , Aberrações Cromossômicas , Metilação de DNA/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Terapia de Alvo Molecular , Neoplasias Neuroepiteliomatosas/patologia , Análise de Componente Principal , Pirimidinas/farmacologia , Receptor Notch1/metabolismo , Sulfonas/farmacologia , Transcriptoma/genética , Proteína Supressora de Tumor p53/genética
15.
Oncogene ; 38(47): 7249-7265, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31420604

RESUMO

Pancreatic cancer is a deadliest type of malignancy and lacks effective intervention. We here report a potential strategy for treatment of this malignancy by the combination of arsenic trioxide (ATO) and BET bromodomain inhibitor JQ1. These two agents synergistically modulate multistages of autophagy and thus induce apoptosis effectively in pancreatic cancer cells. Our genomic and biochemical data have demonstrated that crosstalks between ER stress and autophagy play crucial roles during ATO-induced apoptosis, in which NRF2 may stand at the crossroad between cell death and survival. This has been further strengthened by our finding that NRF2 depletion renders insensitive cells into sensitive ones in regard to ATO treatment-caused cell death. The knockdown of NRF2 and the addition of JQ1 result in similar molecular/cellular effects in promoting effective ATO-induced apoptosis in cells that are insensitive to ATO treatment alone. Thus, the combination of ATO and JQ1 may represent a new treatment strategy for pancreatic cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Trióxido de Arsênio/farmacologia , Autofagia/efeitos dos fármacos , Azepinas/farmacologia , Neoplasias Pancreáticas/patologia , Triazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Toxicol Lett ; 315: 1-8, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421153

RESUMO

Arsenic trioxide (As2O3) has been used clinically for the treatment of acute promyelocytic leukemia and some solid tumors. However, the mechanisms of its anti-tumor effects are still elusive. Angiogenesis is a key process for tumor initiation, and increasing evidence has supported the role of anti-angiogenesis caused by arsenic in tumor suppression, although the detailed mechanism is not well understood. In the present study, we found that As2O3 significantly inhibited the angiogenesis of human umbilical vein endothelial cells (HUVECs) in vitro, and this was mediated by the upregulation of FoxO3a. Knockdown of FoxO3a could restore the angiogenic ability of HUVECs. Moreover, vascular endothelial cell-specific knockout of FoxO3a in mice could disrupt the anti-angiogenesis effect of As2O3 and endow the tumors with resistance to As2O3 treatments. Our results revealed a new mechanism by which As2O3 suppresses angiogenesis and tumor growth.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Trióxido de Arsênio/farmacologia , Trióxido de Arsênio/uso terapêutico , Proteína Forkhead Box O3/efeitos dos fármacos , Leucemia Promielocítica Aguda/tratamento farmacológico , Regulação para Cima/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Veias Umbilicais/efeitos dos fármacos
17.
Blood Cells Mol Dis ; 79: 102351, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31400712

RESUMO

Acute promyelocytic leukemia (APL) is often accompanied by a potentially devastating coagulopathy. Predictors of thrombohemorrhagic early death (TH-ED)/early bleeding death are not well characterized. In this retrospective study, eleven baseline clinical variables that can be assessed easily and promptly were chosen for evaluation in a cohort of 364 patients with APL who were administered arsenic trioxide (ATO) alone as remission induction therapy. TH-ED was defined as death from bleeding or thrombosis within 30 days after hospital admission. Cox proportional hazards regression model was used for both the univariate and multivariate analyses. Totally, 53 patients died from severe bleeding (51 cases) or thrombosis (2 cases), and at 30 days the cumulative incidences of TH-ED were 14.6%. Six independent risk factors for TH-ED were identified, including relapse, male, white blood cell (WBC) count above 10 × 109/L, fibrinogen level below 1 g/L, D-dimer level above 4 mg/L and increased creatinine level. Increased creatinine level was the most powerful risk factor, followed by WBC count > 10 × 109/L. This study identified risk factors for TH-ED in a large cohort of patients with APL, which enriched clinical information on identifying patients at high risk of TH-ED.


Assuntos
Trióxido de Arsênio/uso terapêutico , Hemorragia/mortalidade , Leucemia Promielocítica Aguda/mortalidade , Trombose/mortalidade , Adulto , Estudos de Coortes , Hemorragia/etiologia , Humanos , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Trombose/etiologia
18.
World Neurosurg ; 131: 252-263.e2, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31376551

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most common and deadly form of brain tumor. After standard treatment of resection, radiotherapy, and chemotherapy, the 5-year survival is <5%. In recent years, research has uncovered several potential targets within the Notch signaling pathway, which may lead to improved patient outcomes. METHODS: A literature search was performed for articles containing the terms "Glioblastoma" and "Receptors, Notch" between 2003 and July 2015. Of the 62 articles retrieved, 46 met our criteria and were included in our review. Nine articles were identified from other sources and were subsequently included, leaving 55 articles reviewed. RESULTS: Of the 55 articles reviewed, 47 used established human GBM cell lines. Seventeen articles used human GBM surgical samples. Forty-five of 48 articles that assessed Notch activity showed increased expression in GBM cell lines. Targeting the Notch pathway was carried out through Notch knockdown and overexpression and targeting δ-like ligand, Jagged, γ-secretase, ADAM10, ADAM17, and Mastermindlike protein 1. Arsenic trioxide, microRNAs, and several other compounds were shown to have an effect on the Notch pathway in GBM. Notch activity in GBM was also shown to be associated with hypoxia and certain cancer-related molecular pathways such as PI3K/AKT/mTOR and ERK/MAPK. Most articles concluded that Notch activity amplifies malignant characteristics in GBM and targeting this pathway can bring about amelioration of these effects. CONCLUSIONS: Recent literature suggests targeting the Notch pathway has great potential for future therapies for GBM.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Proteínas de Neoplasias/antagonistas & inibidores , Receptores Notch/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Proteínas ADAM/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Antineoplásicos/farmacologia , Trióxido de Arsênio/farmacologia , Neoplasias Encefálicas/irrigação sanguínea , Hipóxia Celular , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Glioblastoma/irrigação sanguínea , Humanos , Proteínas Inibidoras de Diferenciação/antagonistas & inibidores , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , MicroRNAs/farmacologia , Microvasos , Terapia de Alvo Molecular/métodos , Netrina-1/antagonistas & inibidores , Niclosamida/farmacologia , Receptores Notch/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Resveratrol/farmacologia , Transdução de Sinais/genética , Tretinoína/farmacologia
19.
G Ital Nefrol ; 36(4)2019 Jul 24.
Artigo em Italiano | MEDLINE | ID: mdl-31373469

RESUMO

Differentiation syndrome (DS), previously known as retinoic acid syndrome or ATRA (all-trans retinoic acid) or ATO (arsenic trioxide) syndrome, is a life-threatening complication of the therapy with differentiating agents in patients with acute promyelocytic leukemia (APL). The latter is a rare subtype of acute myeloid leukemia and represents a hematological emergency. The clinical manifestations of DS, after induction therapy with differentiating agents, include unexplained fever, acute respiratory distress with interstitial pulmonary infiltrates, unexplained hypotension, peripheral edema, congestive heart failure and acute renal failure. The therapy is based on early intravenous administration of high-dose dexamethasone, in order to counteract the cytokine storm responsible for the DS. Among the supportive measures for the management of DS, furosemide (in 87% of patients) and dialysis (12% of patients) are used to manage acute renal failure, peripheral and pulmonary edema. We describe a case of acute renal failure, treated with haemodialysis, in a young patient with APL and an early and severe DS after induction therapy. This is a rare condition, not well known among nephrologists, where early recognition and treatment are crucial for the prognosis.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Antineoplásicos/efeitos adversos , Trióxido de Arsênio/efeitos adversos , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/efeitos adversos , Lesão Renal Aguda/terapia , Adulto , Dexametasona/uso terapêutico , Edema/induzido quimicamente , Febre de Causa Desconhecida/induzido quimicamente , Humanos , Hipotensão/induzido quimicamente , Quimioterapia de Indução/efeitos adversos , Masculino , Diálise Renal , Síndrome do Desconforto Respiratório do Adulto/induzido quimicamente , Síndrome
20.
Chemistry ; 25(57): 13189-13196, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31336004

RESUMO

Previous results revealed that arsenic trioxide might be used as promising therapeutic agent for the treatment of some solid tumours as atypical teratoid rhabdoid tumours (ATRT). However, in order to become an approved drug for solid tumour treatment, the active formulation has to get more efficient and feasible-but at the same time less toxic. One of the possibilities to achieve this dichotomy is to use nanomedicine tools. Herein, we report on the Zn-based metal-organic framework ZIF-8 (Zeolitic Imidazolate Framework-8) which turned out to be a promising candidate for the delivery of AsIII species. It conjointly features a high drug loading capacity and a prominent pH-triggered release behaviour. AsIII -loaded ZIF-8 nanoparticles coated and non-coated with polyethylene glycol were studied by XRPD, IR, Raman, TGA, TEM, EDX, CHN-elemental analysis, sorption analysis and ICP-OES, and their cytotoxicity was evaluated in vitro.


Assuntos
Trióxido de Arsênio/química , Nanopartículas/química , Neoplasias/fisiopatologia , Polietilenoglicóis/química , Zeolitas/química , Sistemas de Liberação de Medicamentos , Concentração de Íons de Hidrogênio
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