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2.
J Exp Bot ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31680166

RESUMO

Plasma membrane proton pumps play a crucial role in maintaining ionic homeostasis in salt-resistant Populus euphratica under saline conditions. High levels of NaCl (200 mM) induced PeHA1 expression in P. euphratica roots and leaves. We isolated a 2022-bp promoter fragment upstream of the translational start of PeHA1 from P. euphratica. The promoter-reporter construct PeHA1-pro::GUS was transferred to tobacco plants, demonstrating that ß-glucuronidase activities increased in root, leaf, and stem tissues under salt stress. DNA affinity purification sequencing revealed that PeWRKY1 protein targeted the PeHA1 gene. We assessed the salt-induced transcriptional response of PeWRKY1 and its interaction with PeHA1 in P. euphratica. PeWRKY1 binding to the PeHA1 W-box in promoter region was verified by a yeast one-hybrid assay, electrophoretic mobility shift assay, luciferase reporter assay, and virus-induced gene silencing. Transgenic tobacco plants overexpressing PeWRKY1 had improved expression of NtHA4, which has a cis-acting W-box in the regulatory region, and H+ pumping activity in both in vivo and in vitro assays. We conclude that salt stress upregulated PeHA1 transcription due to the binding of PeWRKY1 to the W-box in the promoter region of PeHA1. Thus, we conclude that enhanced H+ pumping activity enabled salt-stressed plants to retain Na+ homeostasis.

3.
Immunity ; 51(5): 930-948.e6, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31604687

RESUMO

Generation of the first T lymphocytes in the human embryo involves the emergence, migration, and thymus seeding of lymphoid progenitors together with concomitant thymus organogenesis, which is the initial step to establish the entire adaptive immune system. However, the cellular and molecular programs regulating this process remain unclear. We constructed a single-cell transcriptional landscape of human early T lymphopoiesis by using cells from multiple hemogenic and hematopoietic sites spanning embryonic and fetal stages. Among heterogenous early thymic progenitors, one subtype shared common features with a subset of lymphoid progenitors in fetal liver that are known as thymus-seeding progenitors. Unbiased bioinformatics analysis identified a distinct type of pre-thymic lymphoid progenitors in the aorta-gonad-mesonephros (AGM) region. In parallel, we investigated thymic epithelial cell development and potential cell-cell interactions during thymus organogenesis. Together, our data provide insights into human early T lymphopoiesis that prospectively direct T lymphocyte regeneration, which might lead to development of clinical applications.

4.
Clin Rheumatol ; 38(10): 2747-2756, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31165341

RESUMO

OBJECTIVES: To evaluate the efficacy and safety of interleukin 17 (IL-17) inhibitors in two rheumatoid arthritis (RA) populations: biologic-naïve or tumor necrosis factor inhibitor inadequate responders (TNF-IR). METHOD: A systematic search was performed in major electronic databases to identify relevant randomized controlled trials (RCTs) reporting the American College of Rheumatology 20% (ACR20), ACR50, ACR70 responses and adverse events (AEs) of IL-17 inhibitors versus placebo in patients with RA. We divided these patients into two subgroups: biologic-naïve or TNF-IR. The meta-analysis was performed using Review Manager 5.3 software. Results were expressed as risk ratio (RR) with pertinent 95% confidence interval (95% CI). RESULTS: Ten studies with a total of 2499 patients were included. For biologic-naïve patients, ACR50 and ACR70 responses were significantly better with IL-17 inhibitors than placebo (RR = 1.71, 95% CI 1.23-2.38, P = 0.001 and RR = 2.63, 95% CI 1.10-6.25, P = 0.03, respectively), but ACR20 responses for IL-17 inhibitors were not statistically superior to placebo (RR = 1.34, 95% CI 0.94-1.91, P = 0.11). For TNF-IR, IL-17 inhibitors were effective in achieving ACR20 (RR = 1.67, 95% CI 1.40-2.00, P < 0.00001), ACR50 (RR = 1.94, 95% CI 1.43-2.63, P < 0.0001), and ACR70 (RR = 2.11, 95% CI 1.26-3.55, P = 0.005) compared to placebo. In the safety analysis, IL-17 inhibitors did not show increased risk of any AEs by comparing to placebo in both biologic-naïve patients and TNF-IR. CONCLUSION: IL-17 inhibitors were effective in the treatment of RA without increased risk of AEs, whether for biologic-naïve patients or TNF-IR. Key Points • In this meta-analysis comparing IL-17 inhibitors with placebo in 2499 rheumatoid arthritis patients, IL-17 inhibitors improved ACR50 and ACR70, but not ACR20, responses in biologic-naïve patients. • IL-17 inhibitors improved ACR20, ACR50, and ACR70 responses in tumor necrosis factor inhibitor inadequate responders.

5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 942-949, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204959

RESUMO

OBJECTIVE: To understand the differentiation of mesoderm-derived Flk1+ cells on different locations of the early mouse embryonic development and to explore the potential of Flk1+ cells to differentiate into mesenchymal lineage, like pericytes during vascular development. METHODS: Based on the Cre-LoxP system conditional knockout study strategy, the Flk1-Cre mice and ROSA26 reporter mice were used for lineage-tracing studies. The fate of the Flk1+ progenitor cells was traced with the GFP+ population. The detection of mesoderm marker Flk1, hematopoietic cell-specific marker CD45, endothelial cell-specific markers CD31, CD144, and Emcn (endomucin), pericyte specific markers PDGFRß and NG2, using the methods of immunohistochemistry, immunofluorescence, and flow cytometry should be combined to solve the concerned problems. RESULTS: Immunohistochemical staining of different fractions of E8.5-10.5 in the early embryogenesis of Flk1-Cre; ROSA26-EYFP mouse lineage showed that there were multiple populations in the Flk1+ cell-derived GFP+ population surrounding hematopoietic sites, such as dorsal aortas, limb buds and yolk sac. In addition to hematopoietic cells, the CD31+/Emcn+ typical endothelial cells distributed specifically along the blood vessel wall, there were many types of cell populations, such as mesenchymal-like cells. The immunofluorescence demonstrated that the cells of this group are neither hematopoietic, non-endothelial cells around the blood vessels, which are NG2+ pericytes. FACS analysis also confirmed that Flk1+ cells contributed to pericytes. In addition, in different hematopoietic sites of the embryo, a small population of CD31+CD140B+ cell populations with a mesenchymal-like morphology was observed in the GFP+ population. CONCLUSION: In the early stages of embryogenesis, mesoderm-derived Flk1+ populations not only contribute to hematopoietic, endothelial, and muscle lineages, but also have a differentiation potential for mesenchymal lineage, like pericytes. The presumably observed CD31+CD140B+ cell population may be a group of endothelial cells differentiated from Flk1+ progenitor cells and undergoing an endothelium-to-mesenchymal transition, EndMT, gradually losing the endothelial surface-specific marker and also starting to express a pericyte surface-specific marker.


Assuntos
Linhagem da Célula , Mesoderma , Células-Tronco , Animais , Diferenciação Celular , Camundongos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Saco Vitelino
6.
Zhongguo Zhong Yao Za Zhi ; 44(4): 774-780, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30989891

RESUMO

In this experiment,the antioxidant capacity of raspberry extract and the protective effect on liver injury induced by ConA in mice were investigated. Balb/C male mice were randomly divided into six groups: normal group,model group,bicyclol control group( 200 mg·kg~(-1)),low-dose raspberry extract group( 200 mg·kg~(-1)),middle-dose raspberry extract group( 400 mg·kg~(-1)),and highdose raspberry extract group( 800 mg·kg~(-1)). Each group was intragastrically administered with drugs according to the body weight once a day. Seven days later,all of the groups except for the normal group were treated with ConA( 20 mg·kg~(-1)) through tail vein injection to establish the acute liver injury model. The mice were put to death 8 hours later. The organ indexes were calculated. These rum levels of ALT,AST and LDH and the activities of SOD,CAT,GSH and MDA in liver tissue were detected. HE staining was used to observe the pathological changes of liver tissue in mice. Western blot was used to detect the expressions of Bax,Bcl-2,Nrf2 and Keap-1. The antioxidant capacity of raspberry extract was measured by CAA assay. The results showed that,raspberry extract had a strong antioxidant capacity. Simultaneously,compared with the model group,raspberry extract can significantly improve the pathological conditions of liver,and significantly reduce ALT,AST and LDH activities in serum of liver injury mice( P<0. 01). The activities of SOD,CAT in liver homogenate supernatant were significantly increased in the high-dose group,the content of GSH increased,while the content of MDA was sharply declined in the high-dose group( P<0. 01). Meanwhile,raspberry extract down-regulated the expressions of Bax and Keap-1 and up-regulated the expressions of Bcl-2 and Nrf2. CAA showed that the compound raspberry extract had a strong antioxidant capacity. Therefore,raspberry extract has an obvious protective effect on acute liver injury induced by ConA in mice.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Rubus , Animais , Antioxidantes , Fígado , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Substâncias Protetoras
7.
Carbohydr Polym ; 207: 428-439, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30600025

RESUMO

Herein, we describe a novel amphipathic chitosan derivative (N-octyl-N'-phthalyl-O-phosphoryl chitosan, abbreviated as OPPC) as an effective oral delivery platform for P-gp substrates, especially paclitaxel (PTX). OPPC could readily self-assemble into micelles, solubilize and encapsulate PTX into the hydrophobic inner core of OPPC with superior loading capacity to chitosan. PTX/OPPC micelles possessed improved intestinal epithelial permeability and oral bioavailability of PTX evaluated by in situ perfusion and pharmacokinetic studies. In vivo fluorescence imaging revealed enhanced stability and integrity of OPPC micelles in mice gastrointestine. Furthermore, cellular uptake studies revealed effective transport and accumulation of OPPC micelles loading PTX or rhodamine-123 into Caco-2 cells via clathrin/cavelin-mediated endocytosis and OPPC-mediated P-gp inhibition. Mechanistically, the inhibition of P-gp efflux pumps by OPPC resulted from the reduction of membrane fluidity and decreased P-gp ATPase activity. In summary, OPPC micelles may serve as an efficient and promising delivery system for enhancing oral bioavailability of P-gp substrates.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Quitosana/análogos & derivados , Quitosana/química , Portadores de Fármacos/química , Paclitaxel/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Administração Oral , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Células CACO-2 , Quitosana/síntese química , Quitosana/toxicidade , Regulação para Baixo , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Humanos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Masculino , Fluidez de Membrana/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Micelas , Paclitaxel/administração & dosagem , Paclitaxel/química , Ratos Sprague-Dawley , Solubilidade , Transcitose/efeitos dos fármacos , Verapamil/farmacocinética
8.
Eur J Med Chem ; 163: 787-803, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30579121

RESUMO

Vitamin D receptor (VDR) is recognized as a potential target for the treatment of breast cancer which is the most common malignancy among women in the world. In this study, a series of nonsecosteroidal VDR agonists with a novel diarylmethane skeleton was designed, synthesized and the anti-tumor activities of these compounds were determined. Compound 28 was identified as the most effective agents in reducing the viability of MCF-7 cells, with a low IC50 via the inhibition of cell cycle and induction of apoptosis by regulating the expression of p21, Bcl2 and Bax. In addition, compound 28 showed high VDR-binding affinity and displayed significant VDR-agonistic activities. Further investigation revealed that compound 28 inhibited tumor growth in an orthotopic breast-tumor model without causing hypercalcemia which is the main side effect of secosteroidal VDR modulators. In summary, these findings discovered novel VDR modulators as promising candidates for cancer chemotherapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos/uso terapêutico , Receptores de Calcitriol/agonistas , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/efeitos dos fármacos , Feminino , Humanos , Hidrocarbonetos Aromáticos/farmacologia , Hipercalcemia , Células MCF-7 , Metano , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteína X Associada a bcl-2/efeitos dos fármacos
9.
J Med Chem ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30350999

RESUMO

Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components and results to impairment of liver function. Vitamin D plays a critical role in the development of liver fibrosis as it inhibits transforming growth factor ß1 (TGFß1)-induced excessive deposition of ECM in activated hepatic stellate cells (HSCs). Here, a series of novel nonsecosteroidal Vitamin D receptor (VDR) agonists with phenyl-pyrrolyl pentane skeleton was designed and synthesized. Among them, seven compounds including 15a exhibited more efficient inhibitory activity in collagen deposition and fibrotic gene expression. Histological examination results displayed that compound 15a treatment prevented the development of hepatic fibrosis that induced by carbon tetrachloride (CCl4) injections in mice. In addition, compound 15a, unlike the positive control calcipotriol and 1,25(OH)2D3, did not cause hypercalcemia that is toxic to nerve, heart and many other organs. These findings provide novel insights into drug discoveries for hepatic fibrosis using nonsecosteroidal VDR modulators.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30256913

RESUMO

rTMS and MSCs transplantation both showed therapeutic effects on cognition impairment in vascular dementia model rats. However, whether these two therapies have synergistic effects and the molecular mechanisms remain unclear. In our present study, rats were randomly divided into six groups: control group, sham operation group, VD group, MSC group, rTMS group and MSC+rTMS group. The VD model rats were prepared using a modified 2VO method. rTMS treatment was implemented at a frequency of 5 Hz, the stimulation intensity for 0.5 Tesla, 20 strings every day with 10 pulses per string and six treatment courses. The results of the Morris water maze test showed that the learning and memory abilities of the MSC group, rTMS group and MSC+rTMS group were better than that of the VD group, and the MSC+rTMS group showed the most significant effect. The protein expression levels of BDNF, NR1, LC3-Ⅱ and Beclin-1 were the highest and p62 protein was the lowest in the MSC+rTMS group. Our findings demonstrated that rTMS could further enhance the effect of MSC transplantation on VD rats and provided an important basis for the combined application of MSC transplantation and rTMS to treat VD or other neurological diseases.

11.
Eur J Med Chem ; 157: 1174-1191, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30193216

RESUMO

Modulating the vitamin D receptor (VDR) is an effective way to treat for cancer. We previously reported a potent non-secosteroidal VDR modulator (sw-22) with modest anti-tumor activity, which could be due to its undesirable physicochemical and pharmacokinetic properties. In this study, we investigated the structure-activity and structure-property relationships around the 2'-hydroxyl group of sw-22 to improve the physicochemical properties, pharmacokinetic properties and anti-tumor activity. Compounds 19a and 27b, the potent non-secosteroidal VDR modulators, were identified as the most effective molecules in inhibiting the proliferation of three cancer cell lines, particularly breast cancer cells, with a low IC50 via the distribution of cell cycle and induction of apoptosis by stimulating the expression of p21, p27 and Bax. Further investigation revealed that 19a and 27b possessed favorable rat microsomal metabolic stability (2.22 and 2.3 times, respectively, more stable than sw-22), solubility (43.9 and 50.2 times, respectively, more soluble than sw-22) and in vivo pharmacokinetic properties. In addition, 19a and 27b showed excellent in vivo anti-tumor activity without cause hypercalcemia, which is the main side effect of marketed VDR modulators. In summary, the favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity of 19a and 27b highlight their potential therapeutic applications in cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Pentanos/farmacologia , Receptores de Calcitriol/metabolismo , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Pentanos/síntese química , Pentanos/química , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/antagonistas & inibidores , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/química , Relação Estrutura-Atividade
12.
J Endocrinol ; 2018 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-30121577

RESUMO

Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipogenesis and a target of the thiazolidinedione (TZD) class of antidiabetic drugs; therefore, identifying novel regulators of PPARγ action in adipocytes is essential for the future development of therapeutics for diabetes. MAGE family member D1 (MAGED1), by acting as an adaptor for ubiquitin-dependent degradation pathways and a co-factor for transcription, plays an important role in neural development, cell differentiation, and circadian rhythm. Here, we showed that MAGED1 expression was downregulated during adipogenesis and loss of MAGED1 promoted preadipocyte proliferation and differentiation in vitro. MAGED1 bound to PPARγ and suppressed the stability and transcriptional activity of PPARγ. Compared to wildtype littermates, MAGED1-deficient mice showed increased levels of PPARγ protein and its target genes, more CD29+CD34+Sca-1+ adipocyte precursors, and hyperplasia of white adipose tissues (WATs). Moreover, MAGED1-deficient mice developed late-onset obesity as a result of decreased energy expenditure and physical activity. However, these mice were metabolically healthy as shown by improved glucose clearance and insulin sensitivity, normal levels of serum lipids, and enhanced secretion of adipokines such as leptin and adiponectin. Taken together, our data identify MAGED1 as a novel negative regulator of PPARγ activity, adipogenesis, and insulin sensitivity in mice. MAGED1 might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance.

13.
J Med Chem ; 61(7): 3059-3075, 2018 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-29518319

RESUMO

The vitamin D3 receptor (VDR), which belongs to the nuclear-receptor superfamily, is a potential molecular target for anticancer-drug discovery. In this study, a series of nonsteroidal vitamin D mimics with phenyl-pyrrolyl pentane skeletons with therapeutic potentials in cancer treatment were synthesized. Among them, 11b and 11g were identified as the most effective agents in reducing the viability of four cancer-cell lines, particularly those of breast-cancer cells, with IC50 values in the submicromolar-concentration range. In addition, 11b and 11g possessed VDR-binding affinities and displayed significant partial VDR-agonistic activities determined by dual-luciferase-reporter assays and human-leukemia-cell-line (HL-60)-differentiation assays. Furthermore, 11b and 11g inhibited tumor growth in an orthotopic breast-tumor model via inhibition of cell proliferation and induction of cell apoptosis. More importantly, 11b and 11g exhibited favorable pharmacokinetic behavior in vivo and did not increase serum calcium levels or cause any other apparent side effects. In summary, 11b and 11g act as novel VDR modulators and may be promising candidates for cancer chemotherapy.

14.
J Sep Sci ; 41(12): 2559-2564, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29582547

RESUMO

This is the third part of a three-part series of papers. In Part I, we presented a method for determining the actual effective geometry of a reference column as well as the thermodynamic-based parameters of a set of probe compounds in an in-house mixture. Part II introduced an approach for estimating the actual effective geometry of a target column by collecting retention data of the same mixture of probe compounds on the target column and using their thermodynamic parameters, acquired on the reference column, as a bridge between both systems. Part III, presented here, demonstrates the retention time transfer and prediction from the reference column to the target column using experimental data for a separate mixture of compounds. To predict the retention time of a new compound, we first estimate its thermodynamic-based parameters on the reference column (using geometric parameters determined previously). The compound's retention time on a second column (of previously determined geometry) is then predicted. The models and the associated optimization algorithms were tested using simulated and experimental data. The accuracy of predicted retention times shows that the proposed approach is simple, fast, and accurate for retention time transfer and prediction between gas chromatography columns.

15.
J Sep Sci ; 41(12): 2553-2558, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29577642

RESUMO

The transfer of thermodynamic parameters governing retention of a molecule in gas chromatography from a reference column to a target column is a difficult problem. Successful transfer demands a mechanism whereby the column geometries of both columns can be determined with high accuracy. This is the second part in a series of three papers. In Part I of this work we introduced a new approach to determine the actual effective geometry of a reference column and thermodynamic-based parameters of a suite of compounds on the column. Part II, presented here, illustrates the rapid estimation of the effective inner diameter (or length) and the effective phase ratio of a target column. The estimation model based on the principle of least squares; a fast Quasi-Newton optimization algorithm was developed to provide adequate computational speed. The model and optimization algorithm were tested and validated using simulated and experimental data. This study, together with the work in Parts I and III, demonstrates a method that improves the transferability of thermodynamic models of gas chromatography retention between gas chromatography columns.

16.
J Sep Sci ; 41(12): 2544-2552, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29579350

RESUMO

The transfer of retention times based on thermodynamic models between columns can aid in separation optimization and compound identification in gas chromatography. Although earlier investigations have been reported, this problem remains unsuccessfully addressed. One barrier is poor predictive accuracy when moving from a reference column or system to a new target column or system. This is attributed to challenges associated with the accurate determination of the effective geometric parameters of the columns. To overcome this, we designed least squares-based models that account for geometric parameters of the columns and thermodynamic parameters of compounds as they partition between mobile and stationary phases. Quasi-Newton-based algorithms were then used to perform the numerical optimization. In this first of three parts, the model used to determine the geometric parameters of the reference column and the thermodynamic parameters of compounds subjected to separation is introduced. As will be shown, the overall approach significantly improves the predictive accuracy and transferability of thermodynamic data (and retention times) between columns of the same stationary phase chemistry. The data required for the determination of the thermodynamic parameters and retention time prediction are obtained from fast and simple experiments. The proposed model and optimization algorithms were tested and validated using simulated and experimental data.

17.
Onco Targets Ther ; 10: 4753-4763, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29033588

RESUMO

Non-small cell lung cancer (NSCLC) is one of the most common malignancies worldwide, and it occurs at a higher frequency in males. HOXD-AS1, an important cancer-associated long noncoding RNA (lncRNA), contributes to the development and progression of several cancers. However, the exact roles of HOXD-AS1 in NSCLC progression are still unknown. Here, we investigated the underlying mechanisms of HOXD-AS1 in human NSCLC tissues. We found that lncRNA HOXD-AS1 was specifically upregulated (P<0.001) in NSCLC tissues and promoted cancer cell growth by targeting miR-147a. Moreover, HOXD-AS1 expression positively correlated with NSCLC clinical pathologic characteristics (tumor size, P=0.006; tumor stage, P=0.044; recurrence, P=0.031) and survival rate (P=0.003). HOXD-AS1 knockdown reduced proliferation and promoted apoptosis of NSCLC cells. The dual-luciferase reporter assay showed that HOXD-AS1 could negatively regulate the expression of miR-147a. miR-147a inhibition abrogated the effect of HOXD-AS1 knockdown on the proliferation and apoptosis of NSCLC cells. Furthermore, HOXD-AS1 positively regulated the expression of pRB (a tumor suppressor protein) in NSCLC cells. Taken together, our data indicated that HOXD-AS1 might be an oncogenic lncRNA that promotes proliferation of NSCLC and could be a therapeutic target in NSCLC.

18.
Am J Pathol ; 186(8): 2117-2128, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27418549

RESUMO

Duodenum-jejunum gastric bypass (DJB) has been used to treat morbid diabetic patients. However, neither the suitability among patients nor the mechanisms of this surgical treatment is clear. Previously, we reported a new mouse strain named Timo as type 2 diabetes model caused by brain-derived neurotrophic factor (Bdnf) deficiency. In this study, we found that DJB on Timo mice reversed their metabolic abnormalities without altering the expression of Bdnf. Glucose tolerance and insulin sensitivity were improved greatly, along with reduction of fat accumulation in liver and white adipose tissue. The gut flora population was altered by DJB with increased proportion of Firmicutes and decreased Actinobacteria and Proteobacteria in the ileum after surgery. Systemic inflammation in Timo mice was greatly suppressed with less macrophage infiltration and lower tumor necrosis factor-α levels in liver and white adipose tissue after surgery. Interestingly, the alteration of gut microflora abundance and improved metabolism preceded the inflammation alleviation after DJB surgery. These results suggested that DJB can reverse Bdnf deficiency-associated metabolic abnormality. In addition, the reduced inflammation may not be the initial cause for the DJB-associated metabolic and microbiota alterations. The increased BDNF protein levels in hypothalamus and hippocampus may result from microbiota change after DJB surgery.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/deficiência , Diabetes Mellitus Experimental/cirurgia , Diabetes Mellitus Tipo 2/cirurgia , Derivação Gástrica , Microbioma Gastrointestinal , Animais , Western Blotting , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Reação em Cadeia da Polimerase em Tempo Real
19.
Sci Rep ; 6: 26735, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27226137

RESUMO

While apoptosis is essential for male germ cell development, improper activation of apoptosis in the testis can affect spermatogenesis and cause reproduction defects. Members of the MAGE-A (melanoma antigen family A) gene family are frequently clustered in mammalian genomes and are exclusively expressed in the testes of normal animals but abnormally activated in a wide variety of cancers. We investigated the potential roles of these genes in spermatogenesis by generating a mouse model with a 210-kb genomic deletion encompassing six members of the Magea gene cluster (Magea1, Magea2, Magea3, Magea5, Magea6 and Magea8). Male mice carrying the deletion displayed smaller testes from 2 months old with a marked increase in apoptotic germ cells in the first wave of spermatogenesis. Furthermore, we found that Magea genes prevented stress-induced spermatogenic apoptosis after N-ethyl-N-nitrosourea (ENU) treatment during the adult stage. Mechanistically, deletion of the Magea gene cluster resulted in a dramatic increase in apoptotic germ cells, predominantly spermatocytes, with activation of p53 and induction of Bax in the testes. These observations demonstrate that the Magea genes are crucial in maintaining normal testicular size and protecting germ cells from excessive apoptosis under genotoxic stress.


Assuntos
Apoptose/fisiologia , Fertilidade/fisiologia , Antígenos Específicos de Melanoma , Família Multigênica/fisiologia , Espermatogênese/fisiologia , Espermatozoides/metabolismo , Animais , Feminino , Masculino , Antígenos Específicos de Melanoma/genética , Antígenos Específicos de Melanoma/metabolismo , Camundongos
20.
Circ Res ; 118(3): 388-99, 2016 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-26699655

RESUMO

RATIONALE: Aortic aneurysm is a life-threatening cardiovascular disorder caused by the predisposition for dissection and rupture. Genetic studies have proved the involvement of the transforming growth factor-ß (TGF-ß) pathway in aortic aneurysm. Smad4 is the central mediator of the canonical TGF-ß signaling pathway. However, the exact role of Smad4 in smooth muscle cells (SMCs) leading to the pathogenesis of aortic aneurysms is largely unknown. OBJECTIVE: To determine the role of smooth muscle Smad4 in the pathogenesis of aortic aneurysms. METHODS AND RESULTS: Conditional gene knockout strategy combined with histology and expression analysis showed that Smad4 or TGF-ß receptor type II deficiency in SMCs led to the occurrence of aortic aneurysms along with an upregulation of cathepsin S and matrix metallopeptidase-12, which are proteases essential for elastin degradation. We further demonstrated a previously unknown downregulation of matrix metallopeptidase-12 by TGF-ß in the aortic SMCs, which is largely abrogated in the absence of Smad4. Chemotactic assay and pharmacologic treatment demonstrated that Smad4-deficient SMCs directly triggered aortic wall inflammation via the excessive production of chemokines to recruit macrophages. Monocyte/macrophage depletion or blocking selective chemokine axis largely abrogated the progression of aortic aneurysm caused by Smad4 deficiency in SMCs. CONCLUSIONS: The findings reveal that Smad4-dependent TGF-ß signaling in SMCs protects against aortic aneurysm formation and dissection. The data also suggest important implications for novel therapeutic strategies to limit the progression of the aneurysm resulting from TGF-ß signaling loss-of-function mutations.


Assuntos
Aneurisma Aórtico/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteína Smad4/deficiência , Proteína Smad4/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Aneurisma Aórtico/genética , Aneurisma Aórtico/patologia , Aneurisma Aórtico/prevenção & controle , Catepsinas/metabolismo , Linhagem Celular , Quimiocinas/metabolismo , Quimiotaxia , Elastina/metabolismo , Feminino , Predisposição Genética para Doença , Macrófagos/metabolismo , Masculino , Metaloproteinase 12 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Fenótipo , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Proteólise , Interferência de RNA , Ratos , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/deficiência , Receptores de Fatores de Crescimento Transformadores beta/genética , Proteína Smad4/genética , Fatores de Tempo , Transfecção , Regulação para Cima
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