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1.
Biosens Bioelectron ; 176: 112893, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33342693

RESUMO

Accurate detection of circulating tumor cells (CTCs) has a pivotal role in the metastasis monitoring and prognosis of tumor. In this work, an ultrasensitive electrochemical cytosensor was developed based on excellent electrocatalytic materials and a dual recognition strategy. Herein, novel branched PtAuRh trimetallic nanospheres (b-PtAuRh TNS) were synthesized for the first time by a facile one-pot method, which had a huge specific surface area and outstanding catalytic activity. B-PtAuRh TNS linked with aptamers targeting mucin1 (MUC1) were served as signal tags to amplify the signal. As electrode modified material, the nanocomposites of Cabot carbon black (BP2000) and AuNPs were used to improve the electron transfer efficiency of electrode. In addition to using b-PtAuRh TNS labeled anti-MUC1 aptamers as signal probes, anti-EpCAM antibodies were worked as capture probes to achieve dual recognition of target cells. In other words, only cells expressing both MUC1 and EpCAM could produce electrochemical signal. The constructed cytosensor presented a wide linear range (5 - 1 × 106 cells mL-1) and a low detection limit (1 cell mL-1). It was worth noting that the proposed cytosensor could detect CTCs in clinical blood samples. To sum up, the developed cytosensor might become a promising detection platform for cancer diagnosis and tumor metastasis.

2.
Bioresour Technol ; 319: 124163, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33254444

RESUMO

Hydrothermal liquefaction (HTL) of Gracilaria corticata (GC) macroalgae was studied over a series of nickel-iron-layered double oxides (NiFe-LDO) supported on activated bio-char catalysts at 280 °C and different solvents medium. Maximum bio-oil yield (56.2 wt%) was found with 5%Ga/NiFe-LDO/AC catalyst at 280 °C under ethanol solvent. The catalytic HTL up-gradation decreased the bio-char yield significantly. However the bio-oil quality significantly improved with using the 5%Ga/NiFe-LDO/AC catalyst. Also, improved performance with higher amount of bio-oil and lower amounts of bio-char and gas were achieved, which is due the several reactions happening during the HTL process. Catalytic HTL also revealed that introducing NiFe-LDO nanosheets into the activated char could result in NiFe-LDO/AC catalysts of higher surface area and increased active sites. Being impregnated by 5%Ga, catalysts with improved acid sites and thereby, advanced deoxygenation and aromatization activities were achieved. Hence Ga/NiFe-LDO/AC could be considered as a promising catalyst HTL bio-oil upgrading.


Assuntos
Gracilaria , Alga Marinha , Biocombustíveis , Biomassa , Óleos Vegetais , Polifenóis , Temperatura , Água
3.
Artigo em Inglês | MEDLINE | ID: mdl-33242673

RESUMO

PURPOSE: The study aimed to investigate the effects of caspofungin (CAS) combined with aspirin (ASP) or verapamil (VPL) on the sensitivity of Candida albicans under planktonic and biofilm conditions. METHODS: A total of 39 clinical strains were utilized to construct the biofilms of C. albicans. The drug sensitivity of ASP or VPL combined with CAS on C. albicans was analyzed by M27-A4 broth microdilution method. The MIC50 values were obtained and fractional inhibitory concentration index (FICI) was calculated. Afterwards, C. albicans ZY22 was selected for time-growth curve analysis, and ZY15 and ZY 22 were used for time-kill curve analysis. RESULTS: Under planktonic condition, MIC50 of CAS was 0.0313-8 µg/mL after CAS alone treatment, while MIC50 of CAS was decreased to 0.0313-4 µg/mL after CAS combined with ASP or VPL. Under biofilm condition, MIC50 of CAS was 0.125-16 µg/mL when CAS alone treated, whereas MIC50 of CAS after CAS combined with ASP or VPL treatment was changed to 0.0625-16 µg/mL or 0.0625-8 µg/mL. FICI results showed that synergistic interactions between CAS and ASP under planktonic and biofilm conditions were severally observed in 17 and 16 strains. However, synergistic interactions between CAS and VPL under planktonic and biofilm conditions were respectively shown in 19 and 23 strains. Additionally, 8000 µg/mL ASP or 8 µg/mL VPL combined with CAS had better inhibitory effects on C. albicans. CONCLUSION: ASP and VPL may be the sensitizer for CAS, and the antifungal effects of CAS may be sensitized by 8000 µg/mL ASP or 8 µg/mL VPL against C. albicans under planktonic and biofilm conditions.

4.
J Environ Radioact ; 222: 106325, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32892899

RESUMO

The current spatial distribution of the risk of terrestrial gamma radiation in China were investigated by using spatial interpolation. And the driving factors influence on the terrestrial gamma radiation dose (TGRD) distribution were identified using the geographic detector, a new statistical method based on the nonlinear hypothesis. The results showed that the values of TGRD were range from 60 to 195 nGy h-1 with the average of 86.5 nGy h-1, and the higher values were recorded in Qingahi-Tibet Plateau, which were all within the range of background value in China. In addition, the radiological indices, ELCR (Excess Lifetime Cancer Risk), TGRD and AEDE (Annual Effective Dose Equivalent) were also within the acceptable range of values by risk assessment. The results by use of the geographic detector showed that sunshine duration, atmosphere pressure, altitude, and rainfall condition have closely related to the TGRD distribution. In addition, these meteorological factors and altitude had more impact on TGRD than the air pollution-related factors. Our study can provide useful information on studying the influence mechanism of the TGRD distribution, the variability of the natural terrestrial gamma radiation in China, and exposure data for risk assessment from low dose chronic exposures.


Assuntos
Raios gama , Monitoramento de Radiação , Poluentes Radioativos do Solo , Radiação de Fundo , China , Doses de Radiação , Medição de Risco , Tibet
5.
Mol Cell Endocrinol ; 518: 111025, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32916194

RESUMO

Insulin gene mutation is the second most common cause of neonatal diabetes (NDM). It is also one of the genes involved in maturity-onset diabetes of the young (MODY). We aim to investigate molecular behaviors of different INS gene variants that may correlate with the clinical spectrum of diabetes phenotypes. In this study, we concentrated on two previously uncharacterized MODY-causing mutants, proinsulin-p.Gly44Arg [G(B20)R] and p.Pro52Leu [P(B28)L] (a novel mutant identified in one French family), and an NDM causing proinsulin-p.(Cys96Tyr) [C(A7)Y]. We find that these proinsulin mutants exhibit impaired oxidative folding in the endoplasmic reticulum (ER) with blocked ER export, ER stress, and apoptosis. Importantly, the proinsulin mutants formed abnormal intermolecular disulfide bonds that not only involved the mutant proinsulin, but also the co-expressed WT-proinsulin, forming misfolded disulfide-linked proinsulin complexes. This impaired the intracellular trafficking of WT-proinsulin and limited the production of bioactive mature insulin. Notably, although all three mutants presented with similar defects in folding, trafficking, and dominant negative behavior, the degrees of these defects appeared to be different. Specifically, compared to MODY mutants G(B20)R and P(B28)L that partially affected folding and trafficking of co-expressed WT-proinsulin, the NDM mutant C(A7)Y resulted in an almost complete blockade of the ER export of WT-proinsulin, decreasing insulin production, inducing more severe ER stress and apoptosis. We thus demonstrate that differences in cell biological behaviors among different proinsulin mutants correlate with the spectrum of diabetes phenotypes caused by the different INS gene mutations.

6.
Cancer Res ; 80(17): 3677-3691, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32651260

RESUMO

Macrophages play important roles in both physiologic and pathologic processes and arise from successive waves of embryonic and adult hematopoiesis. Monocyte-derived macrophages (MOMF) exert distinct functions under pathologic conditions, and leukemia-associated macrophages (LAM) show considerable diversities in activation and functional phenotype. However, their origin and pathologic roles have not been well elucidated. Here we used wild-type and CCR2-/- mice to study the pathologic roles of monocyte-derived LAM in extramedullary tissues in models of Notch1-induced T-cell acute lymphoblastic leukemia (T-ALL). MOMF existed in the resting liver and spleen. In the spleen, Ly6C+ monocytes gave rise to the Ly6C+ macrophage subset. Furthermore, an increase of monocyte-derived LAM, including the Ly6C+ subset, was detected in the extramedullary tissues in leukemic mice. More monocyte-derived LAM, including Ly6C+ LAM, was detected in the spleens of leukemic mice transplanted with exogeneous mononuclear cells. Moreover, Ly6C+ LAM exhibited increased M1-related characteristics and contributed to sterile inflammation. In CCR2-/- leukemic mice, reduced Ly6C+ LAM, relieved sterile inflammation, and reduced distribution of leukemia cells were detected in extramedullary tissues. In addition, monocyte-derived Ly6C+ LAM expressed high levels of CCL8 and CCL9/10. Blocking CCR1 and CCR2 relieved hepatosplenomegaly and inhibited the extramedullary distribution of leukemia cells in T-ALL mice. Collectively, our findings reveal the multifaceted pathologic roles of monocyte-derived LAM in T-ALL progression. SIGNIFICANCE: This study links monocyte-derived leukemia-associated macrophages with noninfectious inflammation and extramedullary distribution of leukemia cells during leukemia progression, providing new insight into macrophage-based immunotherapy in leukemia.

7.
Ecotoxicol Environ Saf ; 197: 110607, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32304922

RESUMO

Estimation of critical load (CL) is important for soil environmental management and pollution prevention. We developed a mass balance-based dynamic critical load (DCL) model, which improved the model performance, applicability and functionality compared with the traditional one. Paddy soils in two typical fields in central south China and two scenarios were chosen as case studies. The result of case study showed that atmospheric deposition was the main source of Cd, Cu, Pb, and Zn in the soils, with percentage contributions ranging from 59.9 to 79.8%. Crop uptake, particularly the rice straw harvest, was the primary output pathway, accounting for 35.1-71.2% of the total output flux. The critical loads also known as annual input limits (Imax) of heavy metals in the paddy soils were calculated by the developed DCL model. For example, the Imax of Cd was recommended as 0.05 kg ha-1 in the paddy soils under the default scenario for a protection period of 40 years, and that became 0.12 kg ha-1 and 0.17 kg ha-1 under the straw removal scenario in the two typical fields, respectively. The scenario simulation suggested that the straw removal strategy reduced the total concentrations of heavy metals (Ct) in the soils and notably increased the Imax. Meanwhile, the sensitivity analysis indicated that the changes of Ct and Imax can be controlled by adjusting the partition coefficient (Kd), plant uptake factor (PUF) and input flux. The mass balance-based DCL model provides a reference method to establish the standard for controlling heavy metal inputs to agricultural soil, this will be helpful to develop strategies for the prevention of soil contamination.


Assuntos
Metais Pesados/análise , Poluentes do Solo/análise , Agricultura , Monitoramento Ambiental , Modelos Teóricos , Oryza , Solo
8.
Cancer Lett ; 482: 44-55, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32278814

RESUMO

Although targeted therapy using tyrosine kinase inhibitors (TKIs) has made remarkable progress in treating chronic myeloid leukemia (CML), this disease remains largely incurable, warranting further investigation of new therapeutic strategies. BCR-ABL is a highly specific tumor antigen in CML and provides an attractive opportunity for vaccination therapy. Exogenous antigens must be presented on MHC class I molecules-via a process termed cross-presentation-to activate specific cytotoxic T lymphocyte response. The relative efficiency of cross-presentation is determined in part by the ability of dendritic cells (DCs) to internalize and present antigens. Here, we present a novel tool that uses cytoplasmic transduction peptide (CTP) to facilitate the internalization of antigens by DCs in an endocytosis-independent manner, which greatly enhances the efficiency of antigen presentation, thereby inducing stronger cytotoxic activity to ensure the elimination of CML cells. The data suggest that CTP-fused CML-specific peptides can be applied in vaccination therapies for CML patients.

9.
Chemosphere ; 252: 126529, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32220718

RESUMO

Magnetic ferrite/biochar composites are a kind of promising adsorbents due to their high adsorption efficiency and facile magnetic separation; however, their synthesis is associated with high cost and secondary environmental impacts. In this study, a novel Mn-Zn ferrite/biochar composite (MZF-BC) is synthesized via a green two-step biocheaching and hydrothermal method using waste batteries and pine sawdust. Characterization results indicate that the introduced Mn-Zn ferrite particles are successfully embedded and coated on biochar (BC), and synthesized MZF-BC50 with 50% BC content exhibits best performance with a specific surface area of 138.5 m2 g-1, the saturation magnetization of 27.5 emu g-1 and CEC value of 53.2 mmol 100 g-1. The maximum adsorption capacity of Pb2+ is 99.5 mg g-1 based on the Langmuir sorption isotherm study at 298 K, and pseudo-second-order model accurately describes the adsorption process. Regeneration test suggests that MZF-BC50 can be efficiently reused for 6 cycles. In addition, it exhibits a good selective Pb2+ and Cd2+ removal performance in lead-acid battery wastewater. The results illustrate that this newly developed material has low cost and rapid remediation of Pb2+ as good application potential.


Assuntos
Fontes de Energia Elétrica , Chumbo/química , Eliminação de Resíduos/métodos , Adsorção , Carvão Vegetal/química , Compostos Férricos/química , Química Verde , Cinética , Magnetismo , Águas Residuárias , Poluentes Químicos da Água/análise , Madeira/química , Zinco
10.
Haematologica ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32165482

RESUMO

Nucleotides mediate intercellular communication by activating purinergic receptors and take part in various physiological and pathological processes. Abnormal purinergic signaling plays important roles in malignant progression. P2X7, which belongs to the P2X family of purinergic receptors, is abnormally expressed in various types of malignancies including leukemia. However, its role and molecular mechanism in leukemia have not been elucidated. Here, we analyzed the correlation between P2X7 expression and AML clinical outcome; explored the role and mechanism of P2X7 in AML progression by using mouse acute myeloid leukemia (AML), nude mouse xenograft and patient-derived xenograft models. High levels of P2X7 expression were correlated with worse survival in AML. P2X7 was highly expressed in MLL-rearranged AML. Furthermore, P2X7 accelerated the progression of MLL-rearranged AML by both promoting cell proliferation and increasing leukemia stem cell (LSC) levels. Moreover, P2X7 caused upregulation of Pbx3 accounts for its pro-leukemic effects. The P2X7-Pbx3 pathway might also contribute to the progression of other types of leukemia as well as solid tumors with high levels of P2X7 expression. Our study provides new insights into the malignant progression caused by abnormal purinergic signaling.

11.
Mikrochim Acta ; 187(4): 216, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32162013

RESUMO

An integrated electrochemical immunoassay is described for the determination of circulating tumor cells (CTCs). For the first time, Ketjen black (KB), which is a superconductive carbon material, was incorporated with Au nanoparticles (AuNPs) and used to modify the surface of gold electrodes. A cocktail of anti-epithelial cell adhesion molecules (EpCAM) and anti-vimentin antibodies was chosen to capture the CTCs. Palladium-iridium-boron-phosphorus alloy-modified mesoporous nanospheres (PdIrBPMNS) served as a catalytic tag to amplify the current signal. Glycine-HCl (Gly-HCl) was used as an antibody eluent to release and collect the captured CTCs from the electrodes for further clinical research without compromising cell viability. The response of the method increased linearly from 10 to 1 × 106 cells mL-1 CTCs, while the detection limit was calculated to be as low as 2 cells mL-1. This method was successfully used to determine CTCs in spiked blood samples and demonstrated good recovery. Graphical abstractKetjen black/AuNPs was incorporated in the electrochemical platform to enhance the electron transfer ability of the electrode surface. PdIrBP mesoporous nanospheres were used to amplify DPV signal in this assay. The introduction of Gly-HCl realized nondestructive recovery of circulating tumor cells.


Assuntos
Técnicas Biossensoriais , Técnicas Eletroquímicas , Nanosferas/química , Células Neoplásicas Circulantes/patologia , Fuligem/química , Boro/química , Condutividade Elétrica , Humanos , Irídio/química , Paládio/química , Tamanho da Partícula , Fósforo/química , Porosidade , Propriedades de Superfície , Células Tumorais Cultivadas
12.
Chem Asian J ; 15(8): 1182-1201, 2020 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-32012471

RESUMO

Heterogeneous transformation of levulinic acid (LA) to γ-valerolactone (GVL) is regarded as a critical process of the lignocellulose-based biorefinery system. Substantial progress on the catalytic conversion of LA to GVL has been continuously achieved recently. However, the traditional research paradigm typically emphasizes the metal-catalyzed hydrogenation step, but lacks profound insights into the potential impacts of catalyst supports. Herein, an overview of the bifunctional catalytic system classified by representative solid acid supports for LA conversion to GVL is presented, and effects of critical factors on metal- and acid- catalyzed processes are discussed. Particularly, impacts of key issues on catalytic stability are thoroughly summarized and analyzed. Challenges and suggestions are also proposed from the perspective of increases in both catalytic activity and stability. This review potentially contributes to the rational design of high-efficiency catalysts used in the biomass valorization for renewable energy production.

13.
Cancer Lett ; 469: 151-161, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31669202

RESUMO

Blocking the migration of regulatory T cells (Tregs) to the tumor microenvironment is a promising strategy for tumor immunotherapy. Treg accumulation in the leukemic hematopoietic microenvironment (LHME) has adverse impacts on patient outcomes. The mechanism and effective methods of disrupting Treg accumulation in the LHME have not been well established. Here, we studied the distribution and characteristics of Tregs in the LHME, investigated the effects of Treg ablation on leukemia progression, explored the mechanisms leading to Treg accumulation, and studied whether blocking Treg migration to the LHME delayed leukemia progression in MLL-AF9-induced mouse acute myeloid leukemia (AML) models using wildtype (WT) and Foxp3DTR/GFP mice. Increased accumulation of more activated Tregs was detected in the LHME. Inducible Treg ablation prolonged the survival of AML mice by promoting the antileukemic effects of CD8+ T cells. Furthermore, both local expansion and migration accounted for Treg accumulation in the LHME. Moreover, blocking the CCL3-CCR1/CCR5 and CXCL12-CXCR4 axes inhibited Treg accumulation in the LHME and delayed leukemia progression. Our findings provide laboratory evidence for a potential leukemia immunotherapy by blocking the migration of Tregs.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Fatores de Transcrição Forkhead/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Adolescente , Transferência Adotiva , Animais , Antineoplásicos Imunológicos/uso terapêutico , Medula Óssea/patologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Quimiocina CCL3/imunologia , Quimiocina CCL3/metabolismo , Quimiocina CXCL12/imunologia , Quimiocina CXCL12/metabolismo , Criança , Pré-Escolar , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Regulação Leucêmica da Expressão Gênica/imunologia , Técnicas de Introdução de Genes , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Masculino , Maraviroc/farmacologia , Maraviroc/uso terapêutico , Camundongos , Camundongos Transgênicos , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Receptores CCR/antagonistas & inibidores , Receptores CCR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
14.
Med Mycol ; 58(5): 690-697, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711175

RESUMO

Bud emergence 46 (BEM46), a member of the α/ß hydrolase superfamily, has been reported to be essential for polarized growth in Neurospora crassa. However, the role of BEM46 in aspergillus fumigatus (A. fumigatus) remains unclear. In this study, we constructed an A. fumigatus strain expressing BEM46 fused with enhanced green fluorescent protein, and a Δbem46 mutant, to explore the localization and the role of growth of BEM46 in A. fumigatus, respectively. Confocal laser scanning microscopy revealed that BEM46 was dominantly expressed in the sites where hyphae germinated from conidia in A. fumigatus. When compared with the control strain, the Δbem46 mutant exhibited insignificant morphological changes but delayed germination. No significant changes were found regarding the radial growth of both strains in response to various antifungal agents. These results suggest that BEM46 plays an essential role in timely germination in A. fumigatus. From the observation of fluorescence localization, we infer that that BEM46 might be involved in polarized growth in A. fumigatus.

15.
Oncol Rep ; 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33416164

RESUMO

Clinical resistance to ABL tyrosine kinase inhibitor (TKI) imatinib remains a critical issue in the treatment of chronic myeloid leukemia (CML). Transcription factor 7 (TCF7) is one of the main Wnt/ß­catenin signaling mediators. Previous studies have shown that TCF7 is vital for tumor initiation, and targeting TCF7 can reduce drug resistance in many types of cancer. However, the role of TCF7 in CML imatinib­resistant cells is unclear. In the present study, we analyzed the transcriptomic data from CML clinical samples in the Gene Expression Omnibus (GEO) and performed experimental verification in the CML imatinib­resistant cell line K562/G01. We found that the expression of TCF7 was independent of BCR­ABL1 activity. Silencing of TCF7 downregulated the expression levels of CTNNB1, CCND1, and ABCC2, and therefore inhibited proliferation, weakened colony formation, and increased the drug sensitivity of imatinib­resistant cells. After analyzing the transcriptomic data of four groups (Scramble, TCF7_KD, Scramble+imatinib, and TCF7_KD+imatinib) using bioinformatics, we noted that Wnt/ß­catenin and ATP­binding cassette (ABC) transporter signaling pathways were upregulated in imatinib­resistant cells under conventional dose of imatinib, and TCF7 knockdown could neutralize this effect. Next, using ChIP­qPCR, we demonstrated that TCF7 was recruited to the promoter region of ABCC2 and activated gene transcription. In summary, our results highlight that the upregulation of Wnt/ß­catenin and ABC transporter signaling pathways induced by imatinib treatment of resistant cells confers imatinib resistance, and reveal that targeting TCF7 to regulate the Wnt/ß­catenin/TCF7/ABC transporter signaling axis may represent an effective strategy for overcoming imatinib resistance.

16.
Onco Targets Ther ; 12: 10455-10467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819526

RESUMO

Background: Karyopherin-ß1 (KPNB1) belongs to the karyopherin superfamily, which functions as shuttling proteins from the cytoplasm to nuclear. A high level of KPNB1 has been reported in various cancers which promotes cell proliferation and inhibits apoptosis. However, the role of KPNB1 in chronic myeloid leukemia (CML) remains uncertain. Methods: Expression level of KPNB1 in CML patient samples and cell lines was analyzed by Western blotting. The proliferation assays and colony formation assay were used to study the CML cell proliferation when KPNB1 knockdown in vitro. Next, Western blotting was used to evaluate the effects of KPNB1 on E2F1 and other cell cycle regulators. Then, the location of E2F1 was detected by immunofluorescence. Finally, flow cytometry was used to detect the effect of KPNB1 inhibitor importazole (IPZ) on CML cells. Results: In this study, we firstly showed that KPNB1 is over-expressed in CML cells. Targeting KPNB1 with small interfering RNA (siRNA) and IPZ reduced proliferation and induced apoptosis of CML cells. The underlying mechanisms were also investigated that E2F1 nuclear transport was blocked after inhibiting KPNB1 with siRNA, suggesting KPNB1 over-expression mediates the excessive nuclear transport of E2F1 in CML cells. Moreover, the expression of the E2F1 targeted molecule such as c-Myc and KPNA2 was markedly reduced. The IPZ arrested CML cells at G2/M phase and induced cell apoptosis. Conclusion: In summary, our results clearly showed that KPNB1 is over-expressed in CML cells and mediates the translocation of E2F1 into the nucleus of CML cells, thereby inhibition of KPNB1 reduced proliferation and induced apoptosis of CML cells which provides new insights for targeted CML therapies.

17.
Indian J Microbiol ; 59(4): 514-524, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31762516

RESUMO

Vulvovaginal candidiasis (VVC), caused by Candida albicans, affects women's health and life. We aimed to explore the correlation between ERG3 as well as Efg1 mutation/overexpression and azoles-resistance, and the correlation between ERG3 and Efg1 mRNA expression in C. albicans. First, C. albicans was isolated from clinical VVC patients. ERG3 and Efg1 mutations were detected by polymerase chain reaction (PCR) and sequencing, and the expression levels of these two genes were also identified by qRT-PCR. Correlations between mutation/overexpression of ERG3/Efg1 and azoles-resistance as well as ERG3 and Efg1 mRNA expression were analyzed. Based on the ERG3 sequencing, the results showed that there were 2 missense mutation sites, 1 nonsense mutation site, and 4 silent mutation sites, while 1 missense mutation sites, 1 nonsense mutation site, and 12 silent mutation sites were found in Efg1. Furthermore, the mRNA levels of ERG3 gene in the strains sensitive to FCA, ITR or VRC were higher than those in the strains resistant to FCA, ITR, VRC (P < 0.05). While for the mRNA levels of Efg1, susceptible strains were lower than resistant strains. Besides, there was a significant linear negative correlation between ERG3 and Efg1 mRNA expression (r = - 0.614, P < 0.001).

18.
Oncol Rep ; 42(5): 1755-1766, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31432184

RESUMO

Diffuse large B­cell lymphoma (DLBCL), the most common type of non­Hodgkin's lymphoma, is classified into germinal center and activated B cell (ABC) subtypes. The myeloid differentiation primary response gene 88 (MYD88) L265P mutation is the most prevalent oncogenic mutation among patients with ABC DLBCL, the subtype that has the more inferior outcome. MYD88 oligomerization driven by the L265P mutant augments myddosome assembly and triggers the activation of nuclear factor kappa­light­chain­enhancer of activated B cells (NF­κB) signaling, highlighting MYD88 oligomerization as a potential therapeutic target for this malignancy. The synthetic peptidomimetic compound ST2825, which has previously been used as an anti­inflammatory agent, has been reported to inhibit MYD88 dimerization. In the present study, the anticancer effects of ST2825 were investigated using L265P­expressing ABC DLBCL cell lines. Using confocal microscopy and high­molecular­weight fraction experiments, it was revealed that L265P­associated myddosome assembly was disrupted by ST2825. The results also revealed that disrupting myddosome assembly promoted the death of ABC DLBCL cells harboring the L265P mutation, as well as downregulating survival signals, including the inhibition of NF­κB and the suppression of IL­10 and interferon­ß production. Further co­immunoprecipitation studies demonstrated that MYD88 bound to BTK in L265P­DLBCL cells, and that this binding was abrogated following ST2825 treatment. Furthermore, the combination of myddosome­assembly disruption and BTK or BCL­2 signaling inhibition led to synergistic ABC DLBCL cell death, and more robust inhibition of NF­κB activity or increased apoptosis, respectively. The results of the present study provide evidence that the synthetic peptidomimetic compound ST2825, which targets myddosome assembly, may serve as a pharmacological inhibitor. ST2825 has the potential for clinical use in patients with L265P DLBCL, and other B­cell neoplasms driven by activated MYD88 signaling.


Assuntos
Compostos Heterocíclicos com 2 Anéis/farmacologia , Linfoma Difuso de Grandes Células B/genética , Fator 88 de Diferenciação Mieloide/química , Fator 88 de Diferenciação Mieloide/metabolismo , Compostos de Espiro/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Mutação , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/metabolismo , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
19.
FASEB J ; 33(10): 11338-11348, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31311313

RESUMO

Insulin resistance in classic insulin-responsive tissues is a hallmark of type 2 diabetes (T2D). However, the pathologic significance of ß-cell insulin resistance and the underlying mechanisms contributing to defective insulin signaling in ß cells remain largely unknown. Emerging evidence indicates that proinsulin misfolding is not only the molecular basis of mutant INS-gene-induced diabetes of youth (MIDY) but also an important contributor in the development and progression of T2D. However, the molecular basis of ß-cell failure caused by misfolded proinsulin is still incompletely understood. Herein, using Akita mice expressing diabetes-causing mutant proinsulin, we found that misfolded proinsulin abnormally interacted with the precursor of insulin receptor (ProIR) in the endoplasmic reticulum (ER), impaired ProIR maturation to insulin receptor (IR), and decreased insulin signaling in ß cells. Importantly, using db/db insulin-resistant mice, we found that oversynthesis of proinsulin led to an increased proinsulin misfolding, which resulted in impairments of ProIR processing and insulin signaling in ß cells. These results reveal for the first time that misfolded proinsulin can interact with ProIR in the ER, impairing intracellular processing of ProIR and leading to defective insulin signaling that may contribute to ß-cell failure in both MIDY and T2D.-Liu, S., Li, X., Yang, J., Zhu, R., Fan, Z., Xu, X., Feng, W., Cui, J., Sun, J., Liu, M. Misfolded proinsulin impairs processing of precursor of insulin receptor and insulin signaling in ß cells.


Assuntos
Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Proinsulina/metabolismo , Transdução de Sinais/fisiologia , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/metabolismo , Retículo Endoplasmático/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dobramento de Proteína , Receptor de Insulina/metabolismo
20.
J Exp Clin Cancer Res ; 38(1): 224, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138265

RESUMO

BACKGROUND: The bcr-abl fusion gene encodes BCR-ABL oncoprotein and plays a crucial role in the leukemogenesis of chronic myeloid leukemia (CML). Current therapeutic methods have limited treatment effect on CML patients with drug resistance or disease relapse. Therefore, novel therapeutic strategy for CML is essential to be explored and the CRISPR RNA-guided FokI nucleases (RFNs) meet the merits of variable target sites and specificity of cleavage enabled its suitability for gene editing of CML. The RFNs provide us a new therapeutic direction to obliterate this disease. METHODS: Guide RNA (gRNA) expression plasmids were constructed by molecular cloning technique. The modification rate of RFNs on bcr-abl was detected via NotI restriction enzyme digestion and T7 endonuclease 1 (T7E1) assay. The expression of BCR-ABL and its downstream signaling molecules were determined by western blotting. The effects of RFNs on cell proliferation and apoptosis of CML cell lines and CML stem/progenitor cells were evaluated by CCK-8 assay and flow cytometry. In addition, murine xenograft model was adopted to evaluate the capacity of RFNs in attenuating the tumorigenic ability of bcr-abl. RESULTS: The RFNs efficiently disrupted bcr-abl and prematurely terminated its translation. The destruction of bcr-abl gene suppressed cell proliferation and induced cell apoptosis in CML lines and in CML stem/progenitor cells. Moreover, the RFNs significantly impaired the leukemogenic capacity of CML cells in xenograft model. CONCLUSION: These results illustrate that the RFNs can target to disrupt bcr-abl gene and may provide a new therapeutic option for CML patients affiliated by drug resistance or disease relapse.


Assuntos
Desoxirribonucleases/metabolismo , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Edição de Genes/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Animais , Apoptose , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Camundongos , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
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