Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 134
Filtrar
1.
Proteomics ; : e2000144, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33570763

RESUMO

C-C Motif Chemokine 18 (CCL18) belongs to the chemokine CC family and is predominantly secreted by M2-tumor associated macrophage (TAMs). It has been reported to be associated with various diseases and malignancies. Previous studies showed that CCL18 promotes metastasis by activating downstream kinases. However, it remains unknown whether CCL18 regulates post-translational modifications, other than phosphorylation, during tumorigenesis. Here, we demonstrate that CCL18 is up-regulated in non-small cell lung cancer (NSCLC) and is involved in regulating the lysine acetylome in A549 cells. Using the combination of SILAC labeling and high-efficiency acetylation enrichment methods, we identified 1372 lysine acetylation(Kac) sites on 796 proteins in CCL18-treated A549 cells. Among the identified Kac sites, 147 from 126 proteins were down-regulated and 7 from 5 proteins were up-regulated with fold changes more than 2 and the P value less than 0.05. Bioinformatics analysis further showed that the proteins with down-regulated acetylation play critical roles in glycolysis, oxidative phosphorylation (OXPHOS), tricarboxylic acid cycle (TCA), and pentose phosphate pathway (PPP) in A549 cells. These results suggest that CCL18 may be involved in the development of NSCLC by regulating acetylation of the proteins in many fundamental cellular processes, especially the metabolic reprogramming of tumor cells. This article is protected by copyright. All rights reserved.

2.
Bioengineered ; 12(1): 310-324, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33446013

RESUMO

In clinical practice, we found that microRNA (miR)-146a-5p is significantly up-regulated in peripheral blood mononuclear cells (PBMCs) of primary sjögren's syndrome (pSS) patients. In vitro experiments confirmed that miR-146a-5p promotes T helper 17 (Th17) cell differentiation, but the specific mechanism is still unknown. To solve this problem, 20 pSS patients and 20 healthy subjects were enrolled in this study and PBMCs were isolated from their blood. The expression of the membrane IL-23 R (mIL-23 R) in PBMCs was determined. CD3+ T cells were also isolated and used to further analyze the relationship between the ectodomain shedding of mIL-23 R and a disintegrin and metalloprotease 17 (ADAM17). Finally, miR-146a-5p inhibitor and mimics were transfected into PBMCs to evaluate the relationship between ADAM17 and mIL-23 R, and explore the role of mIL-23 R and ADAM17 in Th17 cell differentiation. Our results revealed a significantly increased expression of miR-146a-5p in PBMCs from pSS patients and significantly increased percentage of Th17 cells compared to PBMCs from healthy controls. Under polarization culture conditions, pSS patient-derived PBMCs can more easily differentiate into Th17 cells, which was, to a great extent, attributable to the increased expression of mIL-23 R. Moreover, ADAM17, an ectodomain sheddase of mIL-23 R, was targeted and negatively regulated by miR-146a-5p, which reduced the ectodomain shedding of mIL-23 R. Overall, our results suggested that miR-146a-5p could promote Th17 cell differentiation through targeting and negatively regulating ADAM17. Thus, these results might offer a new approach in the treatment of pSS.

3.
Zhongguo Gu Shang ; 33(11): 1042-7, 2020 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-33269855

RESUMO

OBJECTIVE: To compare the clinical efficacy of three minimally invasive methods of anterior column screw, plate and screw rod system in the treatment of anterior pelvic ring fracture. METHODS: From December 2015 to September 2018, 77 patients with pelvic anterior ring fracture were treated and followed up, including 45 males and 32 females, aged 19 to 73 years. According to AO / OTA classification, there were 26 cases of type B1, 20 cases of type B2, 17 cases of type B3 and 14 cases of type C. According to the different internal fixation methods, they were divided into three groups:anterior column screw group(35 cases), plate group(20 cases), and screw rod system group(22 cases). The operation time, intraoperative fluoroscopy times, blood loss, fracture reduction quality, complications and curative effect of the three groups were compared. RESULTS: All 77 patients were followed up for 12 to 33 (16.5±5.7) months. The operation time, intraoperative blood loss and incision length of anterior column screw group were significantly shorter than those of plate group and screw rod system group, and intraoperative fluoroscopy times of plate group were significantly less than those of anterior column screw group and screw rod system group (P<0.05). There was no significant difference in the quality of fracture reduction and curative effect among the three groups(P>0.05). The incidence of complications was significant different among three group(P<0.05). CONCLUSION: Minimally invasive internal fixation with anterior column screw, plate and screw rod system can obtain good clinical effect, but anterior column screw fixation has less trauma and lower incidence of surgicalcomplications.

4.
Neurosci Res ; 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33309869

RESUMO

During mammalian corticogenesis, Notch signaling is essential to maintain neural stem cells called radial glial cells (RGCs) and the cortical architecture. Because the conventional knockout of either Notch1 or Notch2 causes a neuroepithelial loss prior to neurogenesis, their functional relationship in RGCs remain elusive. Here, we investigated the impacts of single knockout of Notch1 and Notch2 genes, and their conditional double knockout (DKO) on mouse corticogenesis. We demonstrated that Notch1 single knockout affected RGC maintenance in early to mid-neurogenesis whereas Notch2 knockout caused no apparent defect. In contrast, Notch2 plays a role in the RGC maintenance as Notch1 does at the late stage. Notch1 and Notch2 DKO resulted in the complete loss of RGCs, suggesting their cooperative function. We found that Notch activity in RGCs depends on the Notch gene dosage irrespective of Notch1 or Notch2 at late neurogenic stage, and that Notch1 and Notch2 have a similar activity, most likely due to a drastic increase in Notch2 transcription. Our results revealed that Notch1 has an essential role in establishing the RGC pool during the early stage, whereas Notch1 and Notch2 subsequently exhibit a comparable function for RGC maintenance and neurogenesis in the late neurogenic period in the mouse telencephalon.

5.
Microb Cell Fact ; 19(1): 157, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738926

RESUMO

BACKGROUND: Maltoheptaose as malto-oligosaccharides with specific degree of polymerization, has wide applications in food, medicine and cosmetics industries. Currently, cyclodextrinase have been applied as prepared enzyme to prepare maltoheptaose. However, the yield and proportion of maltoheptaose was lower, which is due to limited substrate and product specificity of cyclodextrinase (CDase). To achieve higher maltoheptaose yield, cyclodextrinase with high substrate and product specificity should be obtained. RESULTS: In this study, cyclodextrinase derived from Thermococcus sp B1001 (TsCDase) was successfully expressed and characterized in Bacillus subtilis for the first time. The specific activity of TsCDase was 637.95 U/mg under optimal conditions of 90 °C and pH 5.5, which exhibited high substrate specificity for cyclodextrins (CDs). When the concentration of ß-CD was 8%, the yield of maltoheptaose achieved by TsCDase was 82.33% across all reaction products, which exceeded the yields of maltoheptaose in other recent reports. Among malto-oligosaccharides generated as reaction products, maltoheptaose was present in the highest proportion, about 94.55%. CONCLUSIONS: This study provides high substrate and product specificity of TsCDase. TsCDase is able to prepare higher yield of maltoheptaose through conversion of ß-CD in the food industry.

6.
Aging Dis ; 11(4): 791-800, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32765946

RESUMO

To explore the underlying pathogenic mechanism of Parkinson's disease (PD) with concomitant postural abnormalities (PDPA) through the relationship between its gait and brain function characteristics. PD patients from the neurology outpatient clinic at Ruijin Hospital were recruited and grouped according to whether postural abnormalities (including camptocormia and Pisa syndrome) were present. PD-related scale assessments, three-dimensional gait tests and brain resting-state functional magnetic imaging were performed and analyzed. The gait characteristics independently associated with PDPA were decreased pelvic obliquity angle and progressive downward movement of the center of mass during walking. PDPA features included decreased functional connectivity between the left insula and bilateral supplementary motor area, which was significantly correlated with reduced Berg Balance Scale scores. Functional connectivity between the right insula and bilateral middle frontal gyrus was decreased and significantly correlated with a decreased pelvic obliquity angle and poor performance on the Timed Up and Go test. Moreover, through diffusion tensor imaging analysis, the average fractional anisotropy value of the fibers connecting the left insula and left supplementary motor area was shown to be decreased in PDPA. There is decreased functional connectivity among the insula, supplementary motor area and middle frontal gyrus with structural abnormalities between the left insula and the left supplementary motor area; these changes in brain connectivity are probably among the causes of gait dysfunction in PDPA and provide some clues regarding the pathogenic mechanisms of PDPA.

7.
DNA Cell Biol ; 39(6): 1064-1071, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32255663

RESUMO

Neuroinflammation is a critical mechanism responsible for the progression of Alzheimer's disease (AD). Recent studies reveal that Hippo/Yes-associated protein (YAP) signaling pathway is highly associated with a series of inflammation-related disorders. Glial cell line-derived neurotrophic factor (GDNF), with its neurotrophic and anti-apoptotic functions for nervous system, has been demonstrated to decrease the expression of proinflammatory mediators. Here we investigated whether Hippo/YAP signaling may affect amyloid-ß (Aß)-induced proinflammatory cytokine production in microglial cells and explored its relationship with the anti-inflammation function of GDNF. The results showed that Aß induced a decrease in the expression of YAP in microglia cells. YAP agonist XMU-MP-1 or its overexpression in microglial cells caused decreased expression of proinflammatory cytokines, whereas YAP antagonist Verteporfin or knockdown of YAP had the opposite effect. Treatment with GDNF resulted in upregulation of YAP expression and reduced the production of proinflammatory cytokines. Meanwhile YAP knockdown weakened the function of GDNF in microglial cells. In conclusion, Hippo/YAP pathway plays a critical role in effect of GDNF against Aß-induced inflammatory response in microglia. Targeting GDNF or Hippo/YAP signaling may be promising therapeutic approach for the treatment of AD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Peptídeos beta-Amiloides/farmacologia , Proteínas de Ciclo Celular/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Microglia/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Linhagem Celular , Citocinas/biossíntese , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Interferência de RNA
8.
Artigo em Inglês | MEDLINE | ID: mdl-32070491

RESUMO

Protein binding events on RNA are highly related to RNA secondary structure, which affects post-transcriptional regulation and translation. However, it remains challenging to describe the association between RNA secondary structure and protein binding events. Here, we present Structure Motif Analysis tool (SMAtool), a pipeline that integrates RNA secondary structure and protein binding site information to profile the binding structure preference of each protein. As an example of applying SMAtool, we extracted the RNA-structure and binding site information respectively from the DMS-seq and eCLIP-seq data of the K562 cell-line, and used SMAtool to analyze the structure motif of each RNA binding protein (RBP). This new approach provided results consistent with X-ray crystallography data from the protein data bank (PDB) database, demonstrating that it can help researchers investigate the structure preference of RBP, and understand the role of RNA secondary structure in gene expression. Availability and implementation: https://github.com/QuKunLab/SMAtool.

9.
J Mol Cell Biol ; 12(8): 654-665, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31174204

RESUMO

Error-free cell division depends on the accurate assembly of the spindle midzone from dynamic spindle microtubules to ensure chromatid segregation during metaphase-anaphase transition. However, the mechanism underlying the key transition from the mitotic spindle to central spindle before anaphase onset remains elusive. Given the prevalence of chromosome instability phenotype in gastric tumorigenesis, we developed a strategy to model context-dependent cell division using a combination of light sheet microscope and 3D gastric organoids. Light sheet microscopic image analyses of 3D organoids showed that CENP-E inhibited cells undergoing aberrant metaphase-anaphase transition and exhibiting chromosome segregation errors during mitosis. High-resolution real-time imaging analyses of 2D cell culture revealed that CENP-E inhibited cells undergoing central spindle splitting and chromosome instability phenotype. Using biotinylated syntelin as an affinity matrix, we found that CENP-E forms a complex with PRC1 in mitotic cells. Chemical inhibition of CENP-E in metaphase by syntelin prevented accurate central spindle assembly by perturbing temporal assembly of PRC1 to the midzone. Thus, CENP-E-mediated PRC1 assembly to the central spindle constitutes a temporal switch to organize dynamic kinetochore microtubules into stable midzone arrays. These findings reveal a previously uncharacterized role of CENP-E in temporal control of central spindle assembly. Since CENP-E is absent from yeast, we reasoned that metazoans evolved an elaborate central spindle organization machinery to ensure accurate sister chromatid segregation during anaphase and cytokinesis.

10.
J Mol Cell Biol ; 12(6): 424-437, 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31638145

RESUMO

Ezrin, a membrane-cytoskeleton linker protein, plays an essential role in cell polarity establishment, cell migration, and division. Recent studies show that ezrin phosphorylation regulates breast cancer metastasis by promoting cancer cell survivor and promotes intrahepatic metastasis via cell migration. However, it was less characterized whether there are additional post-translational modifications and/or post-translational crosstalks on ezrin underlying context-dependent breast cancer cell migration and invasion. Here we show that ezrin is acetylated by p300/CBP-associated factor (PCAF) in breast cancer cells in response to CCL18 stimulation. Ezrin physically interacts with PCAF and is a cognate substrate of PCAF. The acetylation site of ezrin was mapped by mass spectrometric analyses, and dynamic acetylation of ezrin is essential for CCL18-induced breast cancer cell migration and invasion. Mechanistically, the acetylation reduced the lipid-binding activity of ezrin to ensure a robust and dynamic cycling between the plasma membrane and cytosol in response to CCL18 stimulation. Biochemical analyses show that ezrin acetylation prevents the phosphorylation of Thr567. Using atomic force microscopic measurements, our study revealed that acetylation of ezrin induced its unfolding into a dominant structure, which prevents ezrin phosphorylation at Thr567. Thus, these results present a previously undefined mechanism by which CCL18-elicited crosstalks between the acetylation and phosphorylation on ezrin control breast cancer cell migration and invasion. This suggests that targeting PCAF signaling could be a potential therapeutic strategy for combating hyperactive ezrin-driven cancer progression.

11.
Sci Rep ; 9(1): 19320, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848415

RESUMO

The drawbacks of low porosity, inferior electrolyte wettability, low thermal dimensional stability and permissive lithium dendrite growth of the conventional microporous polyolefin-based separators hinder their widely application in the high power density and safe Lithium ion batteries. Herein, highly porous polybenzimidazole-based separator is prepared by a facile non-solvent induced phase separation process (NIPS) using water, ethanol, chloroform and ethyl acetate as the coagulation bath solvent, respectively. It was found that the ethanol is suitable to fabricate uniform morphology macroporous separator with the porosity of 92%, electrolyte uptake of 594 wt.%, and strong mechanical strength of 15.9 MPa. In addition, the experimental tests (electrochemical analysis and XPS test) and density functional theory calculation suggest that the electron-rich imidazole ring of polybenzimidazle can enhance Li+ mobility electrostatic attraction interaction while the block the PF6- mobility via electrostatic repulsion interaction. Therefore, high Li+ transference number of 0.76 was obtained for the neat polybenzimidazole-based polymer electrolyte. As a proof of concept, the Li/LiFePO4 cell with the polybenzimidazole-based polymer electrolyte/1.0 M LiPF6- ethylene carbonate/dimethyl carbonate (v:v = 1:1) electrolyte exhibits excellent rate capability of >100 mAh g-1 at 6 C (1 C = 170 mA g-1) and superior cycle stability of 1000 cycles.

12.
Medicine (Baltimore) ; 98(42): e17235, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626084

RESUMO

BACKGROUND: Conflicting results have been reported on the association of poststroke depression with recurrent stroke events. This meta-analysis of prospective studies aims to evaluate whether poststroke depression is an independent predictor of stroke recurrence among stroke patients. METHODS: A systematic search of articles in PubMed and Embase databases from their inception to October 2018 was conducted. Prospective studies reporting risk estimates of stroke recurrence by depression status in stroke patients were included and pooled risk ratio (RR) with 95% confidence intervals (CIs) of stroke recurrence was calculated for patients with or without poststroke depression. RESULTS: Six studies with 4648 stroke patients were finally included, and the prevalence of poststroke depression was found to from 15.9% to 40.5%. The pooled adjusted RR for stroke recurrence in patients suffering from poststroke depression was 1.48 (1.22-1.79) in a fixed-effect model. Subgroup analyses indicated that poststroke depression significantly increased stroke recurrence (RR 1.64; 95% CI, 1.28-2.10) among ischemic stroke patients but not in total stroke patients (RR 1.28; 95% CI, 0.96-1.73). CONCLUSIONS: This meta-analysis suggests that poststroke depression may be an independent predictor of stroke recurrence among ischemic stroke patients. Further studies are required to investigate whether treatment of poststroke depression can reduce the risk of stroke recurrence.


Assuntos
Depressão/epidemiologia , Acidente Vascular Cerebral/psicologia , Idoso , Idoso de 80 Anos ou mais , Depressão/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Recidiva , Fatores de Risco , Sobreviventes/estatística & dados numéricos
13.
Cell Rep ; 28(10): 2517-2526.e5, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484065

RESUMO

The endoplasmic reticulum (ER) membrane protein complex (EMC) is a key contributor to biogenesis and membrane integration of transmembrane proteins, but our understanding of its mechanisms and the range of EMC-dependent proteins remains incomplete. Here, we carried out an unbiased mass spectrometry (MS)-based quantitative proteomic analysis comparing membrane proteins in EMC-deficient cells to wild-type (WT) cells and identified 36 EMC-dependent membrane proteins and 171 EMC-independent membrane proteins. Of these, six EMC-dependent and six EMC-independent proteins were further independently validated. We found that a common feature among EMC-dependent proteins is that they contain transmembrane domains (TMDs) with polar and/or charged residues. Mutagenesis studies demonstrate that EMC dependency can be converted in cells by removing or introducing polar and/or charged residues within TMDs. Our studies expand the list of validated EMC-dependent and EMC-independent proteins and suggest that the EMC is involved in handling TMDs with residues challenging for membrane integration.


Assuntos
Retículo Endoplasmático/metabolismo , Membranas Intracelulares/metabolismo , Proteínas de Membrana/metabolismo , Complexos Multiproteicos/metabolismo , Proteômica , Linhagem Celular , Células HEK293 , Células HeLa , Humanos , Proteínas de Membrana/química , Mutagênese/genética , Domínios Proteicos , Reprodutibilidade dos Testes , Resposta a Proteínas não Dobradas
14.
Angew Chem Int Ed Engl ; 58(38): 13443-13447, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31338946

RESUMO

Axially chiral 2-arylpyrrole frameworks are efficiently accessed through a direct chirality transfer strategy by rapid cyclization of enantioenriched atropisomeric alkenes, which are generated by organocatalytic asymmetric N-alkylation reactions. This approach accommodates a broad scope of substrates with remarkably high chirality transfer efficiency, affording novel atropisomers with a fully substituted pyrrole moiety and high enantiopurities. Given the enantioenriched atropisomeric alkenes, novel heterocyclic 2-arylazepine atropisomers were realized through a rationally designed ene reaction.

15.
Org Lett ; 21(14): 5495-5499, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31257896

RESUMO

Axially chiral amides are usually found in many biologically active compounds and are useful ligands in asymmetric catalysis. Herein, by using the dynamic kinetic resolution approach, an asymmetric allylic alkylation reaction of racemic amide naphthols is disclosed, which leads to generation of the axially chiral naphthamides in good to excellent yields (up to 97%) and enantioselectivities (up to 96:4 e.r.). Density functional theory was used to gain a theoretical understanding of the enantioselectivities in this reaction.


Assuntos
Amidas/química , Naftóis/química , Alquilação , Catálise , Teoria da Densidade Funcional , Cinética , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Termodinâmica
16.
Zhongguo Zhong Yao Za Zhi ; 44(11): 2324-2330, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359659

RESUMO

The aim of this paper was to investigate the preventive effects of Keluoxin Capsules(KLX) on diabetic retinopathy in db/db mice. One hundred male db/db diabetic mice(45-55 g, 8 weeks) were randomly divided into 5 groups(model, KLX low dose, KLX middle dose, KLX high dose, Dobesilate) and 20 male C57 BL/KsJdb~(+/+) were taken as control group. Body weight and fasting blood-glucose were detected every week. Mice were administrated with saline(control and model group), KLX(780, 1 560, 3 120 mg·kg~(-1)·d~(-1), ig), Dobesilate(195 mg·kg~(-1)·d~(-1), ig) for 20 weeks, respectively. At the end of the administration, optical coherence tomography, fundus fluorescein angiography and electroretinogram of the retina were measured. The eyeball was extirpated and retina was isolated to make paraffin section, followed by HE staining and glial fibrillary acidic protein(GFAP) immunohistochemistry. The results indicated that KLX has no obvious effect on body weight and fasting blood level in db/db mice. However, KLX could significantly regulate the thickness of retinal ganglion layer and inner plexiform layer. KLX was able to remarkably reduce the quantity of diabetic microvessel. Meanwhile, KLX could notably improve retinal function. Moreover, KLX could observably modulate the cell arrangement and edema in each layer. There was no markable difference in retina according to the immunochemistry assay. In the present study, KLX exert marked preventive effects on diabetic retinopathy in db/db mice, which provided an experimental evidence for clinical use.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética/tratamento farmacológico , Hipoglicemiantes/farmacologia , Animais , Cápsulas , Angiofluoresceinografia , Masculino , Camundongos , Distribuição Aleatória , Retina/efeitos dos fármacos
17.
J Cancer ; 10(4): 885-892, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30854094

RESUMO

Background: Afatinib is a second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that has been approved by the Food and Drug Administration for the treatment of advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations. We performed a meta-analysis to assess the efficacy and safety of afatinib in advanced NSCLC. Methods: We searched PubMed, PMC database, EMBASE, Cochrane Library and Web of Science to obtain the relevant literature. The efficacy and safety of afatinib was assessed based on progression-free survival (PFS), overall survival (OS), overall response rate (ORR), primary grade 3/4 adverse events and fatal adverse events (FAEs). A subgroup analysis was performed according to control type for all end-points. Results: Seven randomized controlled trials were included, with a total of 3093 patients. The meta-analysis showed that afatinib treatment significantly prolonged PFS in patients compared with control groups (HR = 0.57, 95% CI: 0.42-0.76; P = 0.00), increased OS (HR = 0.91, 95% CI: 0.83-0.99; P = 0.04) and ORR (RR = 1.82, 95% CI: 1.13-2.93; P = 0.01). In terms of safety, afatinib significantly increased the incidence of diarrhea (RR = 8.9, 95% CI: 5.33-14.93; P = 0.00), rash (RR = 7.31, 95% CI: 1.56-34.12; P = 0.01) and stomatitis (RR = 6.45, 95% CI: 1.27-32.78; P = 0.03), compared with the control group. However, there was no significant difference in FAEs (RR = 0.75, 95% CI: 0.38-1.49; P = 0.41). Conclusions: This meta-analysis confirmed that afatinib extended survival, improved response rates and did not increase the risk of treatment-related mortality in advanced NSCLC. As a novel EGFR-TKI, afitinib has significant potential for clinical application.

18.
Org Lett ; 21(5): 1551-1554, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30789736

RESUMO

A pair of enantiomeric polyketides, (+)- and (-)-alternamgin (1), featuring an unprecedented 6/6/6/6/5/6/6 seven ring backbone, were isolated from the endophytic fungi Alternaria sp. MG1. The relative configuration of 1 was determined using X-ray diffraction, and the absolute configurations of (±)-1 were confirmed by comparing the experimental and calculated ECD data. Plausible biosynthetic pathways for 1 were proposed. Compound (-)-1 exhibited moderate necrosis rates to Hela and HepG2 cells, but (+)-1 only showed similar necrosis rates to HepG2 cells.


Assuntos
Alternaria/química , Policetídeos/isolamento & purificação , Células Hep G2/efeitos dos fármacos , Humanos , Estrutura Molecular , Necrose , Policetídeos/química , Estereoisomerismo , Difração de Raios X
19.
Clin Breast Cancer ; 19(2): e283-e296, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30737173

RESUMO

INTRODUCTION: Angiogenesis and epidermal growth factor receptor signaling are potential therapeutic targets in triple negative breast cancer (TNBC). We hypothesized that targeting these critical pathways would prolong progression-free survival with first-line therapy for metastatic TNBC. PATIENTS AND METHODS: We conducted a phase II trial of nab-paclitaxel and bevacizumab, followed by maintenance therapy with bevacizumab and erlotinib, for patients with metastatic TNBC. During induction, the patients received nab-paclitaxel 100 mg/m2 intravenously (days 1, 8, and 15) and bevacizumab 10 mg/kg intravenously (days 1 and 15) every 28 days for 6 cycles. Patients free of progression at 24 weeks received maintenance therapy with bevacizumab 10 mg/kg intravenously every 2 weeks and oral erlotinib 150 mg/d until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were best overall response, overall survival (OS), and adverse events. We explored the measurement of circulating tumor cells as a prognostic marker. RESULTS: A total of 55 evaluable patients were enrolled. The median PFS and OS for the cohort was 9.1 months (95% confidence interval, 7.2-11.1) and 18.1 months (95% confidence interval, 15.6-21.7), respectively. Of the 53 patients with measurable disease, 39 (74%) had experienced a partial response and 10 (19%) had stable disease using the Response Evaluation Criteria In Solid Tumors. The most common toxicities were uncomplicated neutropenia, fatigue, and neuropathy. Decreased circulating tumor cells from baseline to the first assessment correlated with longer PFS and OS. CONCLUSION: Nab-paclitaxel and bevacizumab, followed by maintenance targeted therapy with bevacizumab and erlotinib, resulted in PFS similar to that of other trials. Most patients experienced a partial response (74%). Most patients received maintenance therapy (55%), providing a break from cytotoxic chemotherapy.


Assuntos
Albuminas/administração & dosagem , Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Cloridrato de Erlotinib/administração & dosagem , Paclitaxel/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/efeitos adversos , Inibidores da Angiogênese/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Bevacizumab/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Células Endoteliais/patologia , Cloridrato de Erlotinib/efeitos adversos , Feminino , Humanos , Quimioterapia de Indução , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/patologia , Paclitaxel/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias de Mama Triplo Negativas/sangue , Neoplasias de Mama Triplo Negativas/patologia , Moduladores de Tubulina/administração & dosagem , Moduladores de Tubulina/efeitos adversos
20.
J Agric Food Chem ; 67(7): 1839-1846, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30688448

RESUMO

Fusarium, a large genus of filamentous fungi, is widely distributed in soil and plants. Fusarium is a prolific source of novel chemical constituents with various bioactivities. In search for antibiotics from soil and endophytic fungi, the secondary metabolites of Fusarium avenaceum SF-1502 and Fusarium proliferatum AF-04 were investigated. An alkaloid (1), a depsipeptide (6), and five sesquiterpenoids (7-11) were isolated from the extracts of the soil fungus F. avenaceum SF-1502. Three alkaloids (2-4), a depsipeptide (5), three sesquiterpenoids (9, 11, and 12), a sesterterpene (13), and four 1,4-naphthoquinones (14-17) were also separated from the extract of the green Chinese onion derived fungus F. proliferatum AF-04. Fusaravenin (1) represents the first example of a natural naphthoisoxazole-type zwitter-ionic alkaloid, a naphthoisoxazole formic acid connected with a morpholino carbon skeleton. Cyclonerotriol B (7) is a new cyclonerane sesquiterpene. Another new sesquiterpene, 3ß-hydroxy-ß-acorenol (12), possesses an acorane framework. The known compounds 9 and 11 were found from both fungi. The structures of the new compounds were determined via extensive HR-ESI-MS and comparison between experimental and calculated NMR results. The biological properties of 1-5 and 7-17 were evaluated against eight anthropogenic bacteria, while 1 and 7-11 were also screened for inhibitory effects against four plant pathogen bacteria. The known compounds 8, 9, and 14-17 showed potent antibacterial activities toward some of the tested anthropogenic bacteria.


Assuntos
Alcaloides/isolamento & purificação , Depsipeptídeos/isolamento & purificação , Fusarium/química , Naftoquinonas/isolamento & purificação , Sesquiterpenos/isolamento & purificação , Microbiologia do Solo , Alcaloides/química , Alcaloides/farmacologia , Antibacterianos , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Naftoquinonas/química , Naftoquinonas/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Espectrometria de Massas por Ionização por Electrospray
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA