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1.
Org Lett ; 21(21): 8620-8624, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31609126

RESUMO

A bifunctional catalytic approach for the asymmetric Mannich reaction of glycine iminoesters with N-phosphinoyl imines has been developed. By the combination of metal catalysis and organocatalysis, the vicinal two stereogenic centers were efficiently constructed, affording a wide range of syn-diamino esters in high yields with excellent enantio- and diastereoselectivities (up to >99:1 dr, 99% ee).

2.
J Exp Clin Cancer Res ; 38(1): 427, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31656203

RESUMO

BACKGROUND: A promising strategy to overcome the chemoresistance is the tumor blood vessel normalization, which restores the physiological perfusion and oxygenation of tumor vasculature. Thalidomide (Thal) has been shown to increase the anti-tumor effect of chemotherapy agents in solid tumors. However, it is not yet known whether the synergistic effect of Thal combined with other cytotoxic drugs is attributable to tumor vascular normalization. METHODS: We used two homograft mice models (4 T1 breast tumor model and CT26 colorectal tumor model) to investigate the effect of Thal on tumor growth, microvessel density, vascular physiology, vascular maturity and function, drug delivery and chemosensitivity. Immunofluorescence, immunohistochemistry and scanning electron microscopy were performed to determine the vessel changes. Protein array assay, qPCR and western blotting were used to detect the molecular mechanism by which Thal regulates tumor vascular. RESULTS: Here we report that Thal potently suppressed tumor growth, angiogenesis, hypoxia, and vascular permeability in animal models. Thal also induced a regular monolayer of endothelial cells in tumor vessels, inhibiting vascular instability, and normalized tumor vessels by increasing vascular maturity, pericyte coverage and endothelial junctions. The tumor vessel stabilization effect of Thal resulted in a decrease in tumor vessel tortuosity and leakage, and increased vessel thickness and tumor perfusion. Eventually, the delivery of cisplatin was highly enhanced through the normalized tumor vasculature, thus resulting in profound anti-tumor and anti-metastatic effects. Mechanistically, the effects of Thal on tumor vessels were caused in part by its capability to correct the imbalance between pro-angiogenic factors and anti-angiogenic factors. CONCLUSIONS: Our findings provide direct evidence that Thal remodels the abnormal tumor vessel system into a normalized vasculature. Our results may lay solid foundation for the development of Thal as a novel candidate agent to maximize the therapeutic efficacy of chemotherapeutic drugs for solid tumors.

3.
BMC Plant Biol ; 19(1): 381, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477017

RESUMO

BACKGROUND: Trehalose-6-phosphate phosphatases (TPPs), which are encoded by members of the TPP gene family, can improve the drought tolerance of plants. However, the molecular mechanisms underlying the dynamic regulation of TPP genes during drought stress remain unclear. In this study, we explored the function of an Arabidopsis TPP gene by conducting comparative analyses of a loss-of-function mutant and overexpression lines. RESULTS: The loss-of-function mutation of Arabidopsis thaliana TPPF, a member of the TPP gene family, resulted in a drought-sensitive phenotype, while a line overexpressing TPPF showed significantly increased drought tolerance and trehalose accumulation. Compared with wild-type plants, tppf1 mutants accumulated more H2O2 under drought, while AtTPPF-overexpressing plants accumulated less H2O2 under drought. Overexpression of AtTPPF led to increased contents of trehalose, sucrose, and total soluble sugars under drought conditions; these compounds may play a role in scavenging reactive oxygen species. Yeast one-hybrid and luciferase activity assays revealed that DREB1A could bind to the DRE/CRT element within the AtTPPF promoter and activate the expression of AtTPPF. A transcriptome analysis of the TPPF-overexpressing plants revealed that the expression levels of drought-repressed genes involved in electron transport activity and cell wall modification were upregulated, while those of stress-related transcription factors related to water deprivation were downregulated. These results indicate that, as well as its involvement in regulating trehalose and soluble sugars, AtTPPF is involved in regulating the transcription of stress-responsive genes. CONCLUSION: AtTPPF functions in regulating levels of trehalose, reactive oxygen species, and sucrose levels during drought stress, and the expression of AtTPPF is activated by DREB1A in Arabidopsis. These findings shed light on the molecular mechanism by which AtTPPF regulates the response to drought stress.

4.
Anesthesiology ; 131(5): 1092-1109, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31517640

RESUMO

BACKGROUND: Sevoflurane administered to neonatal rats induces neurobehavioral abnormalities and epigenetic reprogramming of their germ cells; the latter can pass adverse effects of sevoflurane to future offspring. As germ cells are susceptible to reprogramming by environmental factors across the lifespan, the authors hypothesized that sevoflurane administered to adult rats could induce neurobehavioral abnormalities in future offspring, but not in the exposed rats themselves. METHODS: Sprague-Dawley rats were anesthetized with 2.1% sevoflurane for 3 h every other day between postnatal days 56 and 60. Twenty-five days later, exposed rats and nonexposed controls were mated to produce offspring. RESULTS: Adult male but not female offspring of exposed parents of either sex exhibited deficiencies in elevated plus maze (mean ± SD, offspring of both exposed parents vs. offspring of control parents, 35 ± 12 vs. 15 ± 15 s, P < 0.001) and prepulse inhibition of acoustic startle (offspring of both exposed parents vs. offspring of control parents, 46.504 ± 13.448 vs. 25.838 ± 22.866%, P = 0.009), and increased methylation and reduced expression of the potassium ion-chloride ion cotransporter KCC2 gene (Kcc2) in the hypothalamus. Kcc2 was also hypermethylated in sperm and ovary of the exposed rats. Surprisingly, exposed male rats also exhibited long-term abnormalities in functioning of the hypothalamic-pituitary-gonadal and -adrenal axes, reduced expression of hypothalamic and hippocampal Kcc2, and deficiencies in elevated plus maze (sevoflurane vs. control, 40 ± 24 vs. 25 ± 12 s, P = 0.038) and prepulse inhibition of startle (sevoflurane vs. control, 39.905 ± 21.507 vs. 29.193 ± 24.263%, P < 0.050). CONCLUSIONS: Adult sevoflurane exposure affects brain development in male offspring by epigenetically reprogramming both parental germ cells, while it induces neuroendocrine and behavioral abnormalities only in exposed males. Sex steroids may be required for mediation of the adverse effects of adult sevoflurane in exposed males.

5.
PLoS Genet ; 15(9): e1008368, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31518356

RESUMO

Telomere shortening is associated with aging and age-associated diseases. Additionally, telomere dysfunction resulting from telomerase gene mutation can lead to premature aging, such as apparent skin atrophy and hair loss. However, the molecular signaling linking telomere dysfunction to skin atrophy remains elusive. Here we show that dysfunctional telomere disrupts BMP/pSmad/P63 signaling, impairing epidermal stem cell specification and differentiation of skin and hair follicles. We find that telomere shortening mediated by Terc loss up-regulates Follistatin (Fst), inhibiting pSmad signaling and down-regulating P63 and epidermal keratins in an ESC differentiation model as well as in adult development of telomere-shortened mice. Mechanistically, short telomeres disrupt PRC2/H3K27me3-mediated repression of Fst. Our findings reveal that skin atrophy due to telomere dysfunction is caused by a previously unappreciated link with Fst and BMP signaling that could be explored in the development of therapies.

6.
Medicine (Baltimore) ; 98(34): e16787, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441850

RESUMO

BACKGROUND: To determine the diagnostic accuracy of techniques with chronic thromboembolic pulmonary hypertension (CTEPH) patients via a protocol for systemic review and network meta-analysis. METHODS: We will search PubMed, EMBASE, Web of Science, and Google Scholar from inception to October 1, 2018. The reference lists of the retrieved articles are also consulted. Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) will be used to assess the risk of bias in each study. The direct meta-analyses, network meta-analyses, and ranking of competing diagnostic tests will be used by STATA 12.0 and WINBUGS 1.4. Heterogeneity and inconsistency are assessed. RESULTS: This study is ongoing, will be submitted to a peer-reviewed journal publication once completed. CONCLUSION: This study will provide a comprehensive evidence summary of diagnostic test accuracy in detecting the CTEPH, and can help patients and clinicians to select appropriate or best diagnostic test. ETHICS AND COMMUNICATION: No ethical approval and patient consent are required, because it is based on published researches. PROSPERO REGISTRATION NUMBER: CRD42019121279.


Assuntos
Diagnóstico por Imagem/métodos , Hipertensão Pulmonar/diagnóstico , Doença Crônica , Humanos , Imagem por Ressonância Magnética/métodos , Meta-Análise em Rede , Projetos de Pesquisa , Sensibilidade e Especificidade , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tomografia Computadorizada por Raios X/métodos , Cintilografia de Ventilação/Perfusão/métodos
7.
Gene ; 716: 144025, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31394177

RESUMO

BACKGROUND: Existing meta-analysis have shown that the miR-200 family can be taken as a prognostic biomarker for many tumors. However, great heterogeneity was shown in predicting overall survival (OS) and progression-free survival (PFS). Emerging studies indicate that the expression levels of members of the miR-200 family are tissue-specific among various tumor tissues, which may be the main reason of the heterogeneity in predicting survival prognosis of tumor patients with the miR-200 family as biomarkers. By further analysis of heterogeneity of the miR-200 family as a biomarker for predicting survival prognosis of patients with different tumors, we expected to provide an accurate basis for the clinical application of the miR-200 family to predict the prognosis of patients with different tumors. METHODS: Eligible published studies were identified by searching the databases of PubMed, Embase and Web of Science. The clinical data of patients in the studies were pooled, and pooled hazard ratios (HR) with 95% confidence intervals (95% CI) were used to calculate the strength of this association. The expressions of miRNAs were extracted from The Cancer Genome Atlas (TCGA). We presented the expressions of each member in miR-200 family in 15 types of cancer by boxplot, and analyzed the correlation among the members of miR-200 family by Spearman method. Different subgroup analyses were then performed based on the correlation among the members of miR-200 family, and the publication bias was assessed using the funnel plot of the Egger bias indicator test. RESULTS: Of 36 articles, including 15 tumor types and 4644 patients were included to perform meta-analysis. It was found that miR-200 family members can be used as independent protective factors in patients with various tumors but the miR-200 family has a higher heterogeneity in predicting prognosis: OS (HR = 0.82, 95% CI: 0.66-1.03, I2 = 85%, P < 0.01) and PFS (HR = 0.81, 95% CI: 0.57-1.16, I2 = 97%, P < 0.01). The data from TCGA database were used to analyze the expression levels of the miR-200 family and the results showed that the expression of miR-429 in different cancers is very different, and there are significant differences in expression levels compared with other miR-200 family members; the expression levels of miR-200a and miR-200b in various tumor tissues were similar to each other, respectively; miR-200c and miR-141 showed similar expression levels in each of most types of cancer tissues except ovarian cancer (OC). The expression levels of members of the miR-200 family in breast cancer (BRCA), cervical cancer (CESC), colon cancer (COAD), esophageal cancer (ESCA), head and neck cancer (HNSC), lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are relatively stable, but great variations can be found in the expression levels of miR-200 family members in ovarian cancer (OC), liver cancer (LIHC), renal clear cell carcinoma (KIRC) and renal papillary cell carcinoma (KIRP). Cluster analysis of expression of target genes of miR-200 family in different cancers yielded similar results to the expression level of the miR-200 family. Subgroup analysis of OC, LIHC, GC and LUAD based on expression levels and clustering results reduced or even eliminated the heterogeneity of miR-200 family members in predicting patient outcomes. CONCLUSIONS: Our results convincingly demonstrated that the miR-200 family could serve as a prognostic biomarker for cancers mentioned above and has potential value in clinical practice. MiR-200 family as prognostic biomarkers needs to be performed according to different tumor tissues and correlation between members in miR-200 family.


Assuntos
MicroRNAs/metabolismo , Neoplasias/mortalidade , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mineração de Dados , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Prognóstico , Análise de Sobrevida
8.
Medicine (Baltimore) ; 98(33): e16857, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415419

RESUMO

BACKGROUND: Postoperative nausea and vomiting (PONV) are common complications following surgery and anesthesia, conventional drugs can carry some side effect in treating PONV. Acupressure PC6 point has been widely used in clinical, but there still exist controversy towards its effectiveness and safety. We, therefore, design this study to systematically assess the effectiveness and safety of acupressure PC6 point for treating PONV. METHODS AND ANALYSIS: Nine online databases will be searched from their inception to May 2019. We will include randomized controlled trials (RCTs) involving patients with PONV and receiving acupressure PC6 point treatment. Two independent reviewers will be responsible for the selection of studies, data extraction and risk of bias assessment. RevMan V.5.3 software will be used for data synthesis with either a fixed effects model or random effects model depending on the heterogeneity test. Evidence quality will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation system (GRADE). The primary outcome is incidence of postoperative nausea (PON), postoperative vomiting (POV) and PONV events during 0 to 6 hours and after 6 hours of the treatment. The secondary outcome is the number of people who use emergency drugs and the number of people with adverse reactions. A meta-analysis will be conducted if no considerable heterogeneity is detected. The results will be presented as risk ratios with 95% confidence interval (CIs) for dichotomous data and weighted mean differences or standardized mean differences with 95% CIs for continuous data. RESULTS: This study will provide a high-quality evidence to assess the effectiveness and safety of acupressure PC6 point for patient with PONV. CONCLUSION: This review will provide up-date evidence of whether acupressure of PC6 point is an effective and safe intervention for PONV. PROSPERO registration number: CRD42019135598.


Assuntos
Acupressão/métodos , Náusea e Vômito Pós-Operatórios/terapia , Pontos de Acupuntura , Antieméticos/efeitos adversos , Antebraço , Humanos , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisão Sistemática como Assunto
9.
Med Sci Monit ; 25: 5738-5746, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31373336

RESUMO

BACKGROUND miR-214-3p has been found to inhibit proliferation and migration in cancer cells. The objective of this study was to determine whether ARHGEF12 is involved in miR-214-3p-mediated suppression of proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). MATERIAL AND METHODS PASMCs were cultured under normoxia or hypoxia. miR-214-3p mimics or inhibitors were transiently transfected into PASMCs. Proliferation, apoptosis, and migration of PASMCs were evaluated using MTT assay, flow cytometry, and Boyden chamber apparatus. Western blot analysis was used to examine expression of Rho guanine nucleotide exchange factor 12 (ARHGEF12), c-fos, c-jun, and caspase-3. Luciferase reporter assay was used to test the direct regulation of miR-214-3p on the 3'-untranslated region (UTR) of ARHGEF12. RESULTS miR-214-3p was significantly upregulated in hypoxia-treated PASMCs. Knockdown of miR-214-3p significantly attenuated hypoxia-induced proliferation and migration in PASMCs and promoted apoptosis, whereas this effect was aggravated by overexpression of miR-214-3p. In addition, dual-luciferase reporter assay demonstrated that ARHGEF12 is a direct target gene of miR-214-3p. The protein levels of ARHGEF12 were downregulated after knockdown of miR-214-3p in PASMCs. Rescue experiment results indicated that decreased proliferation of PASMCs resulted from knockdown of miR-214-3p were partially reversed by silencing of ARHGEF12 by siRNA. Furthermore, knockdown of miR-214-3p reduced expression of c-jun and c-fos, but increased expression of caspase-3 in PASMCs under hypoxia. CONCLUSIONS In conclusion, these results indicate that miR-214-3p acts as a novel regulator of hypoxia-induced proliferation and migration by directly targeting ARHGEF12 and dysregulating c-jun and c-fos in PASMCs, and may be a potential therapeutic target for treating pulmonary hypertension.

11.
Nucleic Acids Res ; 47(16): 8485-8501, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31304534

RESUMO

Endogenous retroviruses (ERVs) contribute to ∼10 percent of the mouse genome. They are often silenced in differentiated somatic cells but differentially expressed at various embryonic developmental stages. A minority of mouse embryonic stem cells (ESCs), like 2-cell cleavage embryos, highly express ERV MERVL. However, the role of ERVs and mechanism of their activation in these cells are still poorly understood. In this study, we investigated the regulation and function of the stage-specific expressed ERVs, with a particular focus on the totipotency marker MT2/MERVL. We show that the transcription factor Zscan4c functions as an activator of MT2/MERVL and 2-cell/4-cell embryo genes. Zinc finger domains of Zscan4c play an important role in this process. In addition, Zscan4c interacts with MT2 and regulates MT2-nearby 2-cell/4-cell genes through promoting enhancer activity of MT2. Furthermore, MT2 activation is accompanied by enhanced H3K4me1, H3K27ac, and H3K14ac deposition on MT2. Zscan4c also interacts with GBAF chromatin remodelling complex through SCAN domain to further activate MT2 enhancer activity. Taken together, we delineate a previously unrecognized regulatory axis that Zscan4c interacts with and activates MT2/MERVL loci and their nearby genes through epigenetic regulation.

12.
Br J Nutr ; : 1-16, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31309901

RESUMO

We aimed to investigate the trends of breast milk lutein concentrations at different times and their relationship with dietary lutein intake during the 12 weeks after delivery. Breast milk samples were collected from 37 mothers at 4, 8, and 12 weeks postpartum. A HPLC detection method was used to measure breast milk lutein concentrations. Dietary intake was assessed using a food frequency questionnaire (FFQ), and then dietary lutein intake was calculated. The correlations between dietary lutein intake and breast milk lutein concentrations during lactation were investigated by Pearson's correlation coefficient. General linear regression models were used to evaluate the optimal regression equation. The mean values of dietary lutein intake at 4, 8, and 12 weeks postpartum were 5.22 ± 3.60, 7.28 ± 4.30, and 7.33 ± 4.24 (mg/d), respectively. The mean values of breast milk lutein concentrations at 4, 8, and 12 weeks postpartum were as follows: 46.41 ± 41.36, 57.96 ± 40.00, and 62.33 ± 30.10 (µg/L), respectively. Breast milk lutein concentrations were positively associated with dietary lutein intake at 4 weeks postpartum (r = 0.527, P < 0.05), which was consistent with the positive correlations observed at 8 and 12 weeks postpartum (r = 0.444, P < 0.05; r = 0.468, P < 0.05) by the sensitivity analysis. Increased dietary lutein intake can increase the concentration of lutein in the breast milk, and women are recommended to increase their dietary intake of green leafy vegetables and fruits that are rich in lutein during the pregnancy and postpartum periods.

13.
J Pharm Biomed Anal ; 174: 728-733, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31299453

RESUMO

Xiao-Ai-Ping injection (XAP) has been shown to be clinically effective in treatment of gastric carcinoma, liver cancer and lung cancer, when it was combined with anticancer drug paclitaxel (PTX). To analyze the effect of XAP on the pharmacokinetics of PTX, a liquid chromatography-tandem mass spectroscopy (LCMS/MS) assay method was developed and validated to quantify PTX simultaneously and its main metabolite 3'-p-hydroxypaclitaxel (C3'-OHP) in rat plasma. PTX and C3'-OHP were quantified using positive MRM mode. The analysis method was validated for specificity, recovery, carry-over, accuracy, precision, sample stability and dilution integrity under various storage conditions. The pharmacokinetic parameters were determined in rats after tail intravenous administration of 6 mg/mL PTX in the absence (control group) or presence of intraperitoneal administration of 10 mL/kg、20 mL/kg XAP (study groups). Compared to control group, the area under the plasma concentration-time curve (AUC) of PTX and C3'-OHP in study groups increased significantly following consecutive administration with XAP for 10 days. In conclusion, pretreatment with XAP enhanced the exposure of PTX and C3'-OHP. There would be herb-drug interaction happening between XAP and PTX in rats.

14.
Mol Immunol ; 112: 266-273, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31212097

RESUMO

Myeloid derived suppressor cells (MDSCs) play a key role in tumor immunosuppressive microenvironment, which helps tumors avoid immune destruction. Blocking the suppressive activities of MDSCs could be a promising strategy to enhance the effect of anti-tumor immunotherapies. In this study, we found that TLR1/TLR2 expression predicted favorable prognosis of lung cancer patients. In the related mice tumor model, TLR1/TLR2 activation by synthetic bacterial lipoprotein (BLP), a TLR1/2 agonist, greatly inhibited tumor growth and selectively decreased monocytic MDSCs (M-MDSCs). Furthermore, BLP treatment redirected M-MDSC differentiation towards M1 macrophage through JNK pathway, and thus blocked the suppressive activity of M-MDSCs in a TLR2-dependent manner. Therefore, our data demonstrated that TLR2 could be a promising biomarker and a potential immunotherapeutic target for lung cancer.


Assuntos
Diferenciação Celular/genética , Macrófagos/fisiologia , Células Supressoras Mieloides/fisiologia , Transdução de Sinais/genética , Receptor 1 Toll-Like/genética , Receptor 2 Toll-Like/genética , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/fisiologia , Células Mieloides , Microambiente Tumoral/genética
15.
Transl Oncol ; 12(9): 1164-1176, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31207547

RESUMO

Telomere length maintenance is essential for cell proliferation, which is particularly prominent in cancer. We validate that the primary colorectal tumors exhibit heterogeneous telomere lengths but mostly (90%) short telomeres relative to normal tissues. Intriguingly, relatively short telomeres are associated with tumor malignancy as indicated by poorly differentiated state, and these tumors contain more cancer stem-like cells (CSLCs) identified by several commonly used markers CD44, EPHB2 or LGR5. Moreover, promyelocytic leukemia (PML) and ALT-associated PML nuclear bodies (APBs) are frequently found in tumors with short telomeres and high proliferation. In contrast, distant normal tissues rarely or only minimally express PML. Inhibition of PML and APBs by an ATR inhibitor decreases proliferation of CSLCs and organoids, suggesting a potential therapeutic target to progressive colorectal tumors. Together, telomere maintenance underling tumor progression is connected with CSLCs.

16.
Inflamm Bowel Dis ; 25(11): 1854-1861, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31050734

RESUMO

BACKGROUND: Vedolizumab effectiveness estimates immediately after Food and Drug Administration (FDA) approval for ulcerative colitis (UC) and Crohn's disease (CD) are limited by use in refractory populations. We aimed to compare treatment patterns and outcomes of vedolizumab in 2 time frames after FDA approval. METHODS: We used 2 data sets for time trend analysis, an academic multicenter vedolizumab consortium (VICTORY) and the Truven MarketScan database, and 2 time periods, May 2014-June 2015 (Era 1) and July 2015-June 2017 (Era 2). VICTORY cumulative 12-month clinical remission, corticosteroid-free remission, and mucosal healing rates, and Truven 12-month hospitalization and surgery rates, were compared between Eras 1 and 2 using time-to-event analyses. RESULTS: A total of 3661 vedolizumab-treated patients were included (n = 1087 VICTORY, n = 2574 Truven). In both cohorts, CD and UC patients treated during Era 2 were more likely to be biologic naïve. Compared with Era 1, Era 2 CD patients in the VICTORY consortium had higher rates of clinical remission (31% vs 40%, P = 0.03) and mucosal healing (42% vs 58%, P < 0.01). These trends were not observed for UC. In the Truven database, UC patients treated during Era 2 had lower rates of inflammatory bowel disease-related hospitalization (22.4% vs 9.6%, P < 0.001) and surgery (17.2% vs 9.4%, P = 0.008), which was not observed for CD. CONCLUSION: Since FDA approval, remission and mucosal healing rates have increased for vedolizumab-treated CD patients, and vedolizumab-treated UC patients have had fewer hospitalizations and surgeries. This is likely due to differences between patient populations treated immediately after drug approval and those treated later.

17.
Toxicol Lett ; 312: 11-21, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31059759

RESUMO

Methamphetamine (METH) is a widely abused illicit psychoactive drug. Our previous study has shown that CCAAT-enhancer binding protein ß (C/EBPß) is an important regulator in METH-induced neuronal autophagy and apoptosis. However, the detailed molecular mechanisms underlying this process remain poorly understood. Previous studies have demonstrated that DNA damage-inducible transcript 4 (DDIT4), Trib3 (tribbles pseudo kinase 3), alpha-synuclein (α-syn) are involved in METH-induced dopaminergic neurotoxicity. We hypothesized that C/EBPß is involved in METH-induced DDIT4-mediated neuronal autophagy and Trib3-mediated neuronal apoptosis. We tested our hypothesis by examining the effects of silencing C/EBPß, DDIT4, Trib3 or α-syn with small interfering ribonucleic acid (siRNA) on METH-induced autophagy and apoptosis in the human neuroblastoma SH-SY5Y cells. We also measured the levels of phosphorylated tuberous sclerosis complex 2 (TSC2) protein and Parkin protein level in SH-SY5Y cells. Furthermore, we demonstrated the effect of silencing C/EBPß on METH-caused neurotoxicity in the striatum of rats by injecting LV-shC/EBPß lentivirus using a stereotaxic positioning system. The results showed that METH exposure increased C/EBPß, DDIT4 protein expression. Elevated DDIT4 expression raised up p-TSC2/TSC2 protein expression ratio, inhibited mTOR signaling pathway, activating cell autophagy. We also found that METH exposure increased the expression of Trib3, α-syn, decreased the Parkin protein expression. Lowering levels of Parkin raised up α-syn expression, which initiated mitochondrial apoptosis by down-regulating anti-apoptotic Bcl-2, followed by up-regulation of pro-apoptotic Bax, resulting in translocation of cytochrome c (cyto c), an apoptogenic factor, from the mitochondria to cytoplasm and activation of caspase-dependent pathways. These findings were supported by data showing METH-induced autophagy and apoptosis was significantly inhibited by silencing C/EBPß, DDIT4, Trib3 or α-syn, or by Parkin over-expression. Based on the present data, a novel of mechanism on METH-induced cell toxicity is proposed, METH exposure increased C/EBPß protein expression, triggered DDIT4/TSC2/mTOR signaling pathway, and evoked Trib3/Parkin/α-syn-related mitochondrial apoptotic signaling pathway. Collectively, these results suggest that C/EBPß plays an important role in METH-triggered autophagy and apoptosis and it may be a potential target for therapeutics in METH-caused neurotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Estimulantes do Sistema Nervoso Central/toxicidade , Metanfetamina/toxicidade , Neurônios/efeitos dos fármacos , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Masculino , Neuroblastoma , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
18.
Artigo em Inglês | MEDLINE | ID: mdl-31094853

RESUMO

BACKGROUND: Currently, the first-line treatment regimen in cirrhotic patients for variceal rebleeding prophylaxis is still under debate. AIM: This study aimed to compare the efficacy and safety of carvedilol plus endoscopic variceal ligation (EVL) and traditional, nonselective ß-blockers (NSBBs) plus EVL in preventing variceal rebleeding. PATIENTS AND METHODS: Studies were found in PubMed, the Cochrane Library, China National Knowledge Infrastructure, Wanfang Med Online, and Wiper Database. Review Manager 5.3 was used to analyze the relevant data. RESULTS: Nine trials including 802 patients were identified (402 for carvedilol and 400 for traditional NSBBs). Carvedilol was more efficacious than traditional NSBBs in decreasing the variceal rebleeding rate [odds ratio (OR): 0.53; 95% confidence interval (CI): 0.38-0.75; P=0.0003], lowering the degree of esophageal varices (OR: 4.40; 95% CI: 2.64-7.34; P<0.00001), decreasing the mean arterial pressure (standard mean difference: -0.35; 95% CI: -0.56 to -0.14; P=0.0009), reducing the total adverse events occurrence (OR: 0.39; 95% CI: 0.28-0.53; P<0.00001), and decreasing drug-related adverse events (OR: 0.37; 95% CI: 0.25-0.56; P<0.00001). No difference was noted between carvedilol and traditional NSBBs with respect to mortality and heart rate (OR: 0.72; 95% CI: 0.43; 1.22; P=0.22 and standard mean difference: 0.09; 95% CI: -0.12 to 0.30; P=0.40, respectively). CONCLUSION: Combined with variceal ligation, carvedilol was more effective and safer than traditional NSBBs in the prevention of rebleeding in cirrhotic patients.

19.
Eur J Pharmacol ; 855: 227-234, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31085236

RESUMO

Phosphatase and tensin homolog (PTEN) plays an important role in the pathogenesis of hypoxic pulmonary hypertension (HPH). A decrease in PTEN expression is associated with the hypermethylation of its promoter. However, whether the demethylation of the PTEN gene could attenuate HPH remains unknown. 5-Aza-2'-deoxycytidine (5-Aza-dC) is a DNA methyltransferase (DNMT) inhibitor. The present study was designed to investigate the effects and mechanisms of 5-Aza-dC on HPH. The proliferation, migration and apoptosis of rat pulmonary artery smooth muscle cells (PASMCs) induced by hypoxia and treated with 5-Aza-dC were detected. The expression of PTEN and DNMTs and the PTEN methylation status of PASMCs were detected. SD rats were randomly divided into normal group, hypoxia group and hypoxia + 5-Aza-dC group. The expression of PTEN was decreased, the expression of DNMTs was increased, and the methylation status of PTEN was increased in hypoxia-induced PASMCs. However, 5-Aza-dC can rescue the decreased PTEN, inhibit DNMT levels in a dose-dependent manner and suppress PTEN methylation. Furthermore, the demethylation of PTEN, which was induced by 5-Aza-dC, inhibited the proliferation, migration and promoted apoptosis in PASMCs. In vivo studies further demonstrated that the expression of PTEN, mean pulmonary artery pressure and right ventricular hypertrophy index in HPH rats was attenuated by 5-Aza-dC. 5-Aza-dC also suppressed the expression of DNMTs and PTEN methylation in the lungs of HPH rats. These results indicated that PTEN promoter methylation status is involved in HPH. 5-Aza-dC, as a DNMT inhibitor, has the potential to attenuate HPH via demethylation of the PTEN promoter.

20.
Nano Lett ; 19(6): 4035-4042, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31082244

RESUMO

Extensive efforts have been devoted to construct a fiber-shaped energy-storage device to fulfill the increasing demand for power consumption of textile-based wearable electronics. Despite the myriad of available material selections and device architectures, it is still fundamentally challenging to develop eco-friendly fiber-shaped aqueous rechargeable batteries (FARBs) on a single-fiber architecture with high energy density and long-term stability. Here, we demonstrate flexible and high-voltage coaxial-fiber aqueous rechargeable zinc-ion batteries (CARZIBs). By utilizing a novel spherical zinc hexacyanoferrate with prominent electrochemical performance as cathode material, the assembled CARZIB offers a large capacity of 100.2 mAh cm-3 and a high energy density of 195.39 mWh cm-3, outperforming the state-of-the-art FARBs. Moreover, the resulting CARZIB delivers outstanding flexibility with the capacity retention of 93.2% after bending 3000 times. Last, high operating voltage and output current are achieved by the serial and parallel connection of CARZIBs woven into the flexible textile to power high-energy-consuming devices. Thus, this work provides proof-of-concept design for next-generation wearable energy-storage devices.

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