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1.
ACS Appl Mater Interfaces ; 11(33): 29641-29654, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31364350

RESUMO

Cancer remains a serious clinical disease awaiting new effective treatment strategies. Autophagy modulation has emerged as a novel and promising pharmacologic target critical to future drug development and anti-cancer therapy applications. Herein, we constructed an in situ autophagy disruption generator to break the balance of autophagy flow for tumor-targeting therapy. Hollow mesoporous manganese trioxide (Mn2O3) nanoparticles (NPs) were synthesized and conjugated with hyaluronic acid (HA) to form tumor-targeting drug carriers. Then, traditional autophagy inhibitor hydroxychloroquine (HCQ) was loaded into the hollow core of HA-Mn2O3, to form a multifunctional theranostics platform (HA-Mn2O3/HCQ). This nanoplatform displayed specific localization and retention in lysosomes after entering tumor cells. The synchronous release of HCQ and manganese ion (Mn2+) induced lysosomal alkalization and osmotic pressure elevation. Significantly greater lysosomal deacidification and autophagy blockade effect emerged after treatment by this nanoplatform, with in vitro tumor inhibition rate of 92.2%. Imaging experiment proved that it could selectively deliver HCQ to tumor sites and further degrade to realize simultaneous release of Mn2+ and HCQ. Micromorphological and immunofluorescence analysis demonstrated that in situ high concentrations of these two substances would achieve effective autophagy blockade. Pharmacodynamics test showed that this nanogenerator displayed the best therapeutic efficacy with 5.08-fold tumor inhibition ratio compared with the HCQ group. Moreover, the generated Mn2+ can be used as T1 contrast agent for visualizing tumor lesions and monitoring therapeutic effects. Overall, the as-made multifunctional drug-delivery system might provide a promising platform for cancer theranostics upon in situ autophagy disruption.

2.
J Chin Med Assoc ; 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31453864

RESUMO

BACKGROUND: Ovarian stimulation with clomiphene (CC) or progestin has been applied for patients with diminished ovarian reserve (DOR). However, it remains unclear which treatment confers greater benefits. This study aimed to compare the outcomes of progestin-primed ovarian stimulation protocol(PPOS)versus CC-primed ovarian stimulation (CPOS) in infertile women with DOR. METHODS: A before-and-after self-controlled study was conducted to retrospectively investigate the data from 50 infertile women with DOR who failed to conceive in their first IVF/ICSI-FET cycle when stimulated with CPOS, and switched to PPOS, in the Reproductive Medicine Center of Changzhou Maternal and Child Health Care Hospital. RESULTS: Our results showed that PPOS significantly suppressed the luteinizing hormone (LH) surge and yielded more satisfactory results in patients with DOR, including increased number of retrieved oocytes, MII mature oocytes, normal fertilized oocytes, cleaved embryos, high-grade embryos, cryopreserved embryos, pregnancy rate, live-birth rate, and decreased miscarriage rates. CONCLUSION: Our study demonstrated that compared with CPOS protocol, PPOS protocol could not only suppress the LH surge but also improved the quantity, particular the quality of oocytes in patients with DOR, suggesting that PPOS treatment is more effective than CPOS for patients with DOR.

3.
Theranostics ; 9(12): 3580-3594, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281499

RESUMO

Tumor microenvironment, such as hypoxia and presence of immune cells, plays a critical role in cancer initiation, growth as well as progression, and seriously affects antitumor effect. Accordingly, we constructed a kind of multifunctional nanoparticles (NPs) with macrophage transformation and oxygen (O2) generation characteristics, to regulate the tumor microenvironment. Methods: In this study, we synthesized mesoporous Prussian blue (MPB) NPs with low molecular weight hyaluronic acid (LMWHA) surface modification (LMWHA-MPB), and discovered that LMWHA-MPB could be used as an in situ macrophages converter and O2 generator. Results: In vitro results showed after uptake by M2 macrophages, LMWHA-MPB displayed the potential in remodeling tumor-associated macrophages (TAMs) phenotype (pro-tumor M2→anti-tumor M1), and anti-metastatic effect on 4T1 cells. Furthermore, in vivo visualized near-infrared (NIR) imaging data proved IR783 labeled LMWHA-MPB NPs could selectively accumulate in tumor sites. Then plenty of O2 generated to alleviate tumor hypoxia via catalytic decomposition of endogenous hydrogen peroxide (H2O2). Based on these outstanding characteristics, LMWHA-MPB NPs were adopted as multifunctional nanocarriers to load sonosensitizer hematoporphyrin monomethyl ether (HMME) for O2 self-provided sonodynamic therapy (SDT). In vivo anti-tumor results showed LMWHA-MPB/HMME could effectively inhibit the proliferation and metastasis of 4T1 tumors by improving tumor microenvironment. Conclusion: The multifunctional NPs can be used as in situ microenvironmental nano-regulators to inhibit the proliferation and metastasis of 4T1 tumor.

4.
Ying Yong Sheng Tai Xue Bao ; 30(6): 1847-1853, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31257755

RESUMO

Ammonium salts, including ammonium nitrate, ammonium sulfate and ammonium hydrogen sulfate, are the main components of secondary inorganic aerosols and play an important role in the formation of haze events. The sources and transformation processes of atmospheric ammonium have received more and more attention. In this study, we modified the previous stable isotope analysis technique by improving the injection volume and adding a pH adjustment step, which gave a rapid and accurate measurement of ammonium nitrogen isotope ratio in atmospheric aerosol samples. Firstly, we added alkaline hypobromite to the extracted solution of the atmospheric aerosol filter samples (0.25 µg·mL-1 ammonium nitrogen in 4 mL) to oxidize ammonium (NH4+) to nitrite (NO2-). Then, after adjusting the pH, nitrite (NO2-) was reduced to nitrous oxide (N2O) by hydroxylamine hydrochloride under pH <0.3. Finally, nitrous oxide (N2O) was analyzed by Precon-GasBench-IRMS system to measure ammonium nitrogen isotope ratio. Our approach required low amount of NH4+ and avoided the use of highly toxic and explosive reagents. Meanwhile, the precision of our method could reach as high as 0.2‰ (n=10). This method could increase the NH4+ reduction efficiency to 100% at a condition of pH <0.3 and satisfy the demands of precision and accuracy for determination of ammonium nitrogen isotope in atmospheric aerosol samples. This method would help us better understand the sources, evolutions, chemical and deposition processes of atmospheric ammonium.


Assuntos
Poluentes Atmosféricos/análise , Compostos de Amônio/análise , Monitoramento Ambiental , Hidroxilamina/química , Isótopos de Nitrogênio/análise , Nitrogênio , Oxirredução , Sais
5.
Int J Mol Med ; 44(1): 253-261, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115551

RESUMO

Oxidative stress serves a critical role in melanocyte death and is considered to be a major cause of vitiligo. The nuclear factor E2­related factor 2 (Nrf2) signaling pathway has an important role in the antioxidative stress mechanisms of melanocytes. Glycyrrhizin (GR) is a derivative of herbal medicines used to treat hepatitis and allergic disease due to its antiviral and anti­allergy effects. GR also activates Nrf2 and induces the expression of heme oxygenase (HO)­1 in macrophages. Whether GR can protect human melanocytes from oxidative stress remains unknown. The present study investigated the potential protective effects of GR against oxidative stress in human melanocytes and the mechanisms involved. Following exposure to 0.5 mM hydrogen peroxide (H2O2), human primary melanocytes were treated with 1 mM GR. Cell viability was determined using a Cell Counting Kit­8 assay, and apoptosis was evaluated by flow cytometry. GR treatment significantly improved cell viability, reduced the apoptotic rate of melanocytes and reduced the level of reactive oxygen species in human melanocytes. Furthermore, GR induced the nuclear translocation of Nrf2 and induced the expression of HO­1 in melanocytes. The knockdown of Nrf2 by small interfering RNA or the inhibition of HO­1 by ZnPP reversed the protective effect of GR on melanocytes against H2O2­induced cytotoxicity and apoptosis. These data demonstrate that GR protects human melanocytes from H2O2­induced oxidative damage via the Nrf2­dependent induction of HO­1, providing evidence for the application of GR in the treatment of vitiligo.

6.
Neurosci Lett ; 705: 159-166, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-31026534

RESUMO

INTRODUCTION: Parkinson's disease (PD) is characterized with reduced dopamine level in the brain, resulting from the nigral degeneration. It is commonly accepted that the function of default mode network (DMN) is disturbed in PD, even in those who have no significant cognitive impairment. However, the relationship between the depletion of dopamine and DMN dysconnectivity is not fully clear. The aim of this study was to investigate the seed-based DMN connectivity and the influence of dopaminergic therapy on the DMN integrity in non-demented PD by using resting-state fMRI. MATERIAL AND METHODS: Resting-state fMRI data was collected from 24 non-demented PD patients before and after taking levodopa and 36 healthy controls (HCs). Functional connectivity (FC) was examined by a seed-based correlation approach. RESULTS: Compared with HCs, decreased DMN connectivity in PD patients was observed, a number of which were significantly improved after taking levodopa therapy. Moreover, by directly comparing the DMN connectivity between ON- and OFF-medication conditions, we found significantly enhanced FC in a set of regions of DMN in the ON- medication condition. Conversely, we also found that the PCC revealed decreased FC with left inferior temporal. CONCLUSION: DMN connectivity was found to be impaired in no-demented PD patients, and levodopa has the ability to impart a normalizing effect on DMN connectivity.

7.
Abdom Radiol (NY) ; 44(8): 2689-2698, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31030244

RESUMO

OBJECTIVES: To investigate the performance of the mean parametric values and texture features based on intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) on identifying pathological complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). METHODS: Pretreatment IVIM-DWI was performed on 41 LARC patients receiving nCRT in this prospective study. The values of IVIM-DWI parameters (apparent diffusion coefficient, ADC; pure diffusion coefficient, D; pseudo-diffusion coefficient, D* and perfusion fraction, f), the first-order, and gray-level co-occurrence matrix (GLCM) texture features were compared between the pCR (n = 9) and non-pathological responder (non-pCR, n = 32) groups. Receiver operating characteristic (ROC) curves in univariate and multivariate logistic regression analysis were generated to determine the efficiency for identifying pCR. RESULTS: The values of IVIM-DWI parameters and first-order texture features did not show significant differences between the pCR and non-pCR groups. The pCR group had lower Contrast and DifVarnc values extracted from the ADC, D, and D* maps, respectively, as well as lower CorrelatD value. Higher CorrelatD*, Correlatf, SumAvergADC, and SumAvergD values were observed in the pCR group. The area under the ROC curve (AUC) values for the individual predictors in univariate analysis ranged from 0.698 to 0.837, with sensitivities from 43.75% to 87.50% and specificities from 66.67 to 100.00%. In multivariate analysis, CorrelatD* (P < 0.001), DifVarncADC (P = 0.024), and DifVarncD (P < 0.001) were the independent predictors to pCR, with an AUC of 0.986, a sensitivity of 93.75%, and a specificity of 100.00%. CONCLUSION: Pretreatment GLCM analysis based on IVIM-DWI may be a potential approach to identify the pathological response of LARC.

8.
Mol Med Rep ; 19(5): 3505-3518, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896852

RESUMO

Transforming growth factor ß1 (TGF­ß1) has been suggested to be a candidate cytokine in the field of bone tissue engineering. Cytokines serve important roles in tissue engineering, particularly in the repair of bone damage; however, the underlying molecular mechanisms remain unclear. In the present study, the effects of TGF­ß1 on the osteogenesis and motility of hFOB1.19 human osteoblasts were demonstrated via the phenotype and gene expression of cells. Additionally, the role of the phosphatidylinositol 3­kinase/protein kinase B/mammalian target of rapamycin/S6 kinase 1 (PI3K/AKT/mTOR/S6K1) signalling pathway in the effects of TGF­ß1 on osteoblasts was investigated. It was demonstrated using Cell Counting Kit­8 and flow cytometry assays that the proliferation of human osteoblasts was promoted by 1 ng/ml TGF­ß1. In addition, alkaline phosphatase activity, Alizarin red staining, scratch­wound and Transwell assays were conducted. It was revealed that osteogenesis and the migration of cells were regulated by TGF­ß1 via the upregulation of osteogenic and migration­associated genes. Alterations in the expression of osteogenesis­ and migration­associated genes were evaluated following pre­treatment with a PI3K/AKT inhibitor (LY294002) and an mTOR/S6K1 inhibitor (rapamycin), with or without TGF­ß1. The results indicated that TGF­ß1 affected the osteogenesis and mineralisation of osteoblasts via the PI3K/AKT signalling pathway. Furthermore, TGF­ß1 exhibited effects on mTOR/S6K1 downstream of PI3K/AKT. The present study demonstrated that TGF­ß1 promoted the proliferation, differentiation and migration of human hFOB1.19 osteoblasts, and revealed that TGF­ß1 affected the biological activity of osteoblasts via the PI3K/AKT/mTOR/S6K1 signalling pathway. Our findings may provide novel insight to aid the development of bone tissue engineering methods for the treatment of bone injury.


Assuntos
Osteoblastos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Linhagem Celular , Movimento Celular , Proliferação de Células , Humanos , Modelos Biológicos , Osteogênese , Serina-Treonina Quinases TOR
9.
Stem Cell Res Ther ; 10(1): 72, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837004

RESUMO

BACKGROUND: The body is unable to repair and regenerate large area bone defects. Moreover, the repair capacity of articular cartilage is very limited. There has long been a lack of effective treatments for osteochondral lesions. The engineered tissue with biphase synthetic for osteochondral repair has become one of the hot research fields over the past few years. In this study, an integrated biomanufacturing platform was constructed with bone marrow mesenchymal stem cells (BMSCs)/porous tantalum (pTa) associated with chondrocytes/collagen membranes (CM) to repair large osteochondral defects in load-bearing areas of goats. METHODS: Twenty-four goats with a large osteochondral defect in the femoral heads of the left hind legs were randomly divided into three groups: eight were treated with chondrocytes/CM-BMSCs/pTa, eight were treated with pure CM-pTa composite, and the other eight goats were untreated. The repair effect was assessed by X-ray, gross observation, and histomorphology for 16 weeks after the operation. In addition, the biocompatibility of chondrocytes/CM-BMSCs/pTa was observed by flow cytometry, CCK8, immunocytochemistry, and Q-PCR. The characteristics of the chondrocytes/CM-BMSCs/pTa were evaluated using both scanning electron microscopy and mechanical testing machine. RESULTS: The integrated repair material consists of pTa, injectable fibrin sealant, and CM promoted adhesion and growth of BMSCs and chondrocytes. pTa played an important role in promoting the differentiation of BMSCs into osteoblasts. Three-dimensional CM maintained the phenotype of chondrocytes successfully and expressed chondrogenic genes highly. The in vivo study showed that after 16 weeks from implantation, osteochondral defects in almost half of the femoral heads had been successfully repaired by BMSC-loaded pTa associated with biomimetic 3D collagen-based scaffold. CONCLUSIONS: The chondrocytes/CM-BMSCs/pTa demonstrated significant therapeutic efficacy in goat models of large osteochondral defect. This provides a novel therapeutic strategy for large osteochondral lesions in load-bearing areas caused by severe injury, necrosis, infection, degeneration, and tumor resection with a high profile of safety, effectiveness, and simplicity.

10.
J Hazard Mater ; 368: 326-335, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30685721

RESUMO

Hydroxyapatite (HA) with perforated porous structure was successfully synthesized using shell powder as the raw material by double interfacial diffusion method. The structure of obtained products was examined by X-ray diffraction, Fourier transform infrared spectrograph, field-emission scanning electron microscopy, transmission electron microscopy, particle size, thermogravimetry and nitrogen adsorption-desorption analysis etc. Results indicate that the perforated porous structure is composed of nanosheets and has high specific surface area (up to 188.5 m2 g-1). Thus, investigation of adsorbing Sr2+ in solution was further examined by discussing factors such as initial pH, ion strength, adsorbent dosage, contact time, initial Sr2+ concentration and temperature. The kinetics and equilibrium adsorption data followed the nonlinear pseudo-second-order kinetic and Liu isotherm models. The maximum removal (%) was up to 98.94% at 313.15 K, and the adsorption process of Sr2+ was endothermic, feasible, and spontaneous in nature as studied via thermodynamic analysis (ΔG° < 0, ΔH° > 0, and ΔS° > 0). A possible adsorption mechanism was proposed. Meanwhile, leaching and desorption experiments was used to evaluate recycling capacity. All the outcomes effectively reveal that the synthesized HA shows great potential in removing Sr2+ from nuclear effluents.

11.
Toxicol In Vitro ; 54: 295-303, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30342220

RESUMO

Our previous study found that 2-aryl-1-cyano-1,2,3,4-tetrahydroisoquinolines (CATHIQs) have excellent anti-cancer activity and obvious apoptosis induction phenomenon. As our continuing research, this study further explored their underlying molecular mechanism of apoptosis induction in cancer cells. Flow cytometry analysis showed that the NB4 cells treated by 1-cyano-2-(2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline or the MKN-45 cells treated by 1-cyano-2-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydroisoquinoline for 48 h were at early stage of apoptosis, and the cell cycle arrest was only slightly affected. Apoptosis rates of the cells significantly increase with the treatment concentration of the compounds. The compounds could significantly decrease the activities of SOD, raise the MDA level and promote the LDH leakage, suggesting that the excessive formation of ROS should be involved in the cell apoptosis. Western blot analysis showed that the compounds improved both Bax/Bcl-2 ratio and cleavages of procaspase-3, promoted efflux of cytochrome c to cytosol and phosphorylation of p38 and JNK, and attenuated phosphorylations of Akt and ERK. Together, inhibitions of PI3K/Akt and ERK and activation of p38 mediated the compounds-induced apoptosis through modulating the mitochondrial pathway and/or ROS production.


Assuntos
Antineoplásicos/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Humanos , L-Lactato Desidrogenase/metabolismo , Malondialdeído/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosfotransferases/metabolismo , Superóxido Dismutase/metabolismo
12.
Curr Alzheimer Res ; 16(2): 135-145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30543171

RESUMO

BACKGROUND: Alzheimer's Disease (AD) is a chronic progressive neurodegenerative disorder in a central nervous system seen. OBJECTIVE: We aimed to study the miR-107 in Alzheimer's Disease (AD) pathology through regulating SYK and NF-κB signaling pathway. METHOD: Bioinformatics analysis was performed to screen NF-κB signaling pathway and differentially expressed genes. The target relationship between miR-107 and SYK was verified by dual luciferase assay. QRT-PCR and western blot analysis were used to verify the expression level of miR-107, SYK and NF- κB signaling pathway related proteins of hippocampus primary neurons. BAY61-3606 and BAY11-7082 were purchased for functional examination. Morris water maze tests were performed to access spatial memory of AD mice with SYK and NF-κB signaling pathway inhibition. Fluorescence microscope dyeing experiment investigated the neurons nuclear form and apoptosis. RESULTS: MiR-107 was lowly expressed while SYK was highly expressed in Tg19959 mouse model. Luciferase Assay confirmed the target relationship in miR-107 and SYK. With the inhibition of miR-107, SYK was up-regulated and the increase of p-p65 and the decrease of p-IκB-α suggested that NF-κB signaling pathway was activated in vitro. Morris water maze test indicated that the spatial memory of Tg19959 mice was increased with the treatment. The result of DAPI staining indicated that the inhibition of SYK or NF-κB signaling pathway reduced the apoptosis of Tg19959 mice neuron cell. CONCLUSION: MiR-107 exerts its effects through suppression of the NF-κB signaling pathway and SYK, the inhibition of SYK and NF-κB signaling pathway can improve spatial memory and suppress cell apoptosis.

13.
Medicine (Baltimore) ; 97(48): e13251, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30508911

RESUMO

BACKGROUND: Successful labor induction depends on the cervical status at the time of induction. Currently, both a Foley catheter and a dinoprostone insert are used for effective cervical ripening. This study compared the efficacy and safety of the intracervical Foley catheter and dinoprostone insert for cervical ripening to achieve successful labor induction. METHODS: PubMed, Embase, and the Cochrane Library were searched from January 2000 to February 2017 for relevant articles. Only published randomized, controlled trials comparing the dinoprostone insert with the Foley catheter were included. RESULTS: Eight trials including 1191 women who received the intracervical Foley catheter balloon and 1199 who received the dinoprostone insert were used for this study. There was no significant difference between the 2 groups regarding the induction-to-delivery (I-D) interval in a random effect model (mean difference, 0.71 hours; 95% confidence interval [CI], -2.50 to 3.91; P = .67). The highly significant heterogeneity (I = 97%) could be explained by the subgroup analysis of the type of Foley catheter and balloon volume. There was no significant difference between the 2 methods regarding the cesarean delivery rate (relative risk, 0.91; 95% CI, 0.78-1.07; P = .24), Apgar score, or side effects, including maternal infection rate, postpartum hemorrhage, and hyperstimulation. No obvious publication bias was found. CONCLUSIONS: According to the cesarean delivery rate, the intracervical Foley catheter balloon was as efficient as the dinoprostone insert. A moderate balloon volume (30 mL) and higher dose of dinoprostone (≥6 mg) were related to shorter I-D intervals. Additionally, there was no significant difference between the two methods regarding maternal or neonatal safety.

14.
Medicine (Baltimore) ; 97(52): e13762, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30593153

RESUMO

BACKGROUND: Cerebral infarction is a commonly dangerous disease also with high morbidity and mortality. Thrombolytic agent is an effective method to treat it, but their relative efficacy and safety are unclear. A network meta-analysis (NMA) will be conducted to resolve this urgent problem. METHODS: The PubMed, Embase, and Cochrane library will be systematically search from their inception to November 2018. All randomized controlled trials (RCTs) will be included this NMA and their risk of bias will be assessed using Cochrane handbook tool. The outcomes of efficacy and safety including: Modified Rankin Scale scores, reperfusion rate, incidence of symptomatic intracerebral hemorrhage and all-cause mortality. A network meta-analysis will be performed using R x64 3.5.1 software and pairwise meta-analysis will be conducted using Stata 12.0 software (Stata Corp., College Station, Texas). Grading of Recommendations Assessment, Development and Evaluation (GRADE) will be used to assess quality of outcomes. RESULTS: The results of NMA will be published in a peer-reviewed journal. CONCLUSION: The NMA will provide a comprehensive evidence summary on thrombolytic agents for patients with cerebral infarction.


Assuntos
Infarto Cerebral/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Meta-Análise em Rede , Revisão Sistemática como Assunto , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Resultado do Tratamento
15.
J Cell Mol Med ; 2018 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-30450766

RESUMO

Tamoxifen (TAM) is a primary drug for treatment of estrogen receptor positive breast cancer. However, TAM resistance remains a serious threat to breast cancer patients and may be attributed to increased stemness of breast cancer. Here, we show that discs large homolog 5 (DLG5) expression is down-regulated in TAM-resistant breast cancer and cells. DLG5 silencing decreased the sensitivity to TAM and increased the frequency and stemness of CD44+ /CD24- breast cancer stem cells (BCSCs) and TAZ, a transducer of the Hippo pathway, expression in MCF7 cells while DLG5 overexpression had opposite effects. TAZ silencing restored the sensitivity to TAM and reduced the frequency and stemness in TAM-resistant breast cancer cells. Taken together, our data indicate that down-regulated DLG5 expression increases the stemness of breast cancer cells by enhancing TAZ expression, contributing to TAM resistance in breast cancer.

16.
J Cell Mol Med ; 22(12): 6148-6156, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30338917

RESUMO

Oxidative stress leads to melanocyte death and has been implicated in the pathogenesis of vitiligo. The nuclear factor, E2-related factor 2 (Nrf2), is a critical transcription factor in protecting cells from oxidative damage. High-mobility group box 1 (HMGB1) is a chromatin-associated nuclear protein and an extracellular damage-associated molecular pattern molecule. Extracellular HMGB1 released from activated immune cells, necrotic or injured cells, becomes a proinflammatory mediator through binding to cell-surface receptors of responding cells. In this study, we investigated the role of HMGB1 from melanocytes in the response to oxidative stress and the mechanism involved. We showed that HMGB1 is expressed by primary normal human epidermal melanocytes (NHEMs). H2 O2 treatment increased cytoplasmic translocation and extracellular release of HMGB1. HMGB1 knockdown by small interfering RNA (siRNA) led to decreased apoptosis of NHEMs. HMGB1 inhibition enhanced the expression of Nrf2 and its target genes. The expression of Nrf2 and its downstream antioxidant genes was downregulated after the supernatant of H2 O2 -treated NHEMs was added to HMGB1-deficient cells. HMGB1 knockdown by siRNA suppressed the expression of the autophagosome marker, LC3, and enhanced p62 expression. Coimmunoprecipitation with Keap1 showed a reduced Nrf2-Keap1 interaction and an increased p62-Keap1 interaction under oxidative stress. These data demonstrated that external stimuli (eg, oxidative stress) may trigger autocrine HMGB1 translocation and release by melanocytes, suppressing the expression of Nrf2 and downstream antioxidant genes to induce melanocyte apoptosis, and thereby participate in the pathological process of vitiligo.

17.
Biochem Soc Trans ; 46(5): 1119-1127, 2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30242115

RESUMO

Restoring blood flow following an acute myocardial infarction saves lives, but results in tissue damage due to ischaemia-reperfusion injury (I/R). Ameliorating this damage is a major research goal to improve recovery and reduce subsequent morbidity due to heart failure. Both the ischaemic and reperfusion phases represent crises of cellular energy provision in which the mitochondria play a central role. This mini-review will explore the rationale and therapeutic potential of augmenting the creatine kinase (CK) energy shuttle, which constitutes the primary short-term energy buffer and transport system in the cardiomyocyte. Proof-of-principle data from several transgenic mouse models have demonstrated robust cardioprotection by either raising myocardial creatine levels or by overexpressing specific CK isoforms. The effect on cardiac function, high-energy phosphates and myocardial injury will be discussed and possible directions for future research highlighted. We conclude that the CK system represents a viable target for therapeutic intervention in I/R injury; however, much needed translational studies will require the development of new pharmacological tools.

18.
Kidney Blood Press Res ; 43(4): 1131-1140, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30016775

RESUMO

BACKGROUND/AIMS: The aim of the study was to investigate clinicopathological characteristics, the role of immunosuppressive therapy and renal outcome in IgA nephropathy (IgAN) patients with hyperuricemia. METHODS: 206 biopsy-proven primary IgAN patients were included between January 2010 and December 2015, and divided into two groups: patients without hyperuricemia (n=122), and patients with hyperuricemia (n=84). The clinicopathological features, response, renal outcome and safety were recorded. In univariate and multivariate models, hyperuricemia-associated pathological factors were analyzed. RESULTS: The patients with hyperuricemia presented higher systolic blood pressure, worse kidney function and more severe time-averaged proteinuria. Proportions of glomerulosclerosis, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, lymphocytes and monocytes infiltration were higher, while the proportion of segmental adhesion was lower in patients with hyperuricemia. By multivariate logistic regression analysis, only tubular atrophy/interstitial fibrosis (T1∼2) (HR=3.969, 95% CI=1.439-10.945, P=0.008) was significantly associated with hyperuricemia. For hyperuricemic patients, the response rate to therapy and renal survival rate were significantly higher in patients that received RAS blockade in combination with immunosuppressive therapy. After RAS blockade treatment, renal survival in the patients with hyperuricemia was worse compared with the patients without hyperuricemia. CONCLUSION: Hyperuricemic IgAN patients presented more severe clinical features. Tubulointerstitial injury could be a pathological feature closely related to hyperuricemia in IgAN. Immunosuppressive therapy and RAS blockade could reduce proteinuria and improve renal outcome in IgAN patients with hyperuricemia.


Assuntos
Glomerulonefrite por IGA/complicações , Hiperuricemia/patologia , Adulto , Feminino , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulosclerose Segmentar e Focal , Humanos , Hiperuricemia/tratamento farmacológico , Imunossupressores/uso terapêutico , Túbulos Renais/lesões , Masculino , Proteinúria , Estudos Retrospectivos , Adulto Jovem
19.
Huan Jing Ke Xue ; 39(7): 3033-3041, 2018 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-29962123

RESUMO

In this study, PM2.5 samples were collected from October to November of 2015 in the northern suburb of Nanjing. The mass concentrations of organic carbon (OC), elemental carbon (EC), and levoglucosan in the samples were analyzed by thermal optical transmittance (TOT) and ion chromatography. The average concentrations of OC and EC were respectively (11.3±4.9) µg·m-3 and (1.1±0.9) µg·m-3. The average total carbon (TC) was 22.9%, and the OC/EC was 7.4. The quality concentrations of PM2.5, OC, EC, and SOC all reflected daytime features, and the correlation between OC and EC was better during the day than at night (correlation coefficients of 0.86 for day and 0.7 for night). By analyzing the mass concentrations of PM2.5, levoglucosan, and SOC, as well as the data of backward trajectories and fire point data, it was determined that the northern suburb of Nanjing is affected by the long-distance transportation of biomass from Hebei and other places from October 13-16. The correlations between levoglucosan and OC, EC, or SOC were significant (correlation coefficients of 0.78, 0.79, and 0.65, respectively), and the contribution of biomass combustion during sampling to OC was 21.9%.

20.
Int J Oncol ; 53(3): 937-948, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29956756

RESUMO

In this study, we aimed to identify the tumor suppressive roles of zinc finger of the cerebellum 1 (ZIC1) in patients with malignant breast neoplasms and to examine the association between ZIC1 and survivin expression. For this purpose, 140 invasive breast cancer specimens, 1,075 RNA breast cancer samples from The Cancer Genome Atlas (TCGA), 6 human breast cancer cell lines and MCF-10A normal breast epithelial cells were selected in order to compare the expression level of ZIC1 with that of survivin via immunohistochemistry and western blot analysis. Subsequently, the MDA-MB-231 and SK-BR3 cells with a lower ZIC1 expression were transfected with rLV-Zic1-PGK-Puro lentivirus or rLV-ZsGreen-PGK­Puro lentivirus in order to observe any alterations in cell proliferation and apoptosis through MTT assay, colony formation assay, mitochondrial membrane potential assay and flow cytometric analysis, and to analyze the modulation of molecular mechanisms by western blot analysis. In addition, xenograft mouse models were constructed to explore the role of ZIC1 in the growth of implanted tumors. The results revealed that ZIC1 negatively correlated with survivin in tumors and cells, and a higher ZIC1 RNA expression indicated a better overall survival in the 1,075 TCGA RNA breast cancer samples. In vitro, the overexpression of ZIC1 inhibited cell proliferation, reduced mitochondrial membrane potential and promoted the apoptosis of the MDA-MB-231 and SK-BR3 breast cancer cells by inactivating the Akt/mTOR/P70S6K pathway, suppressing survivin expression, modulating the cell cycle, releasing cytochrome c (Cyto-c) into the cytosol and activating caspase proteins. In vivo, an elevated ZIC1 expression suppressed the growth of implanted tumors and downregulated survivin expression in tumors. On the whole, the findings of this study demonstrate that ZIC1 plays a tumor suppressive role in breast cancer, by targeting surviving, significantly downregulating its expression.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Inibidoras de Apoptose/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Animais , Apoptose/genética , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Feminino , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Mastectomia , Potencial da Membrana Mitocondrial/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Transdução de Sinais/genética , Survivina , Proteínas Supressoras de Tumor/genética , Ensaios Antitumorais Modelo de Xenoenxerto
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