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2.
Int J Biol Macromol ; 154: 499-510, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32194114

RESUMO

To evaluate if mixed micelles of Dox@FA-BSP-SA/TPGS can allow for the superior antitumor efficiency than Dox@FA-BSP-SA micelles. The complex of doxorubicin (Dox) and sodium cholate was encapsulated into the mixed micelles composed of folate-mediated stearic acid-modified Bletilla striata polysaccharide (FA-BSP-SA) and D-α-tocopheryl polyethylene glycol succinate (TPGS). Its average particle size increased whereas load capacity (LC) and encapsulation efficiency (EE) decreased with the increase of TPGS mass ratio in the mixed micelles. The changes of morphology, particle size and doxorubicin release in vitro demonstrated the pH sensitivity of micelles. FA-BSP-SA/TPGS mixed micelle exhibited average particle size of 147.3 nm, LC of 14.4% and EE of 91.9% for doxorubicin at the weight ratio of 3: 1. The doxorubicin release rate of micelles was faster in pH 5.0 media compared with that in pH 6.0 and 7.4 media. The cytotoxicity in vitro and antitumor efficacy in vivo results of Dox@FA-BSP-SA/TPGS micelle were more superior to that of free doxorubicin and Dox@FA-BSP-SA single micelle. For Dox@FA-BSP-SA/TPGS micelle, the clathrin-mediated endocytosis was the dominant mechanism of intracellular uptake. The FA-BSP-SA/TPGS mixed micelle may be a promising drug delivery system for cancer chemotherapy.

3.
Allergy ; 2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32198890

RESUMO

BACKGROUND: The contribution of B-cell subsets and T-B cell interaction to the pathogenesis of allergic rhinitis (AR) and mechanisms of allergen immunotherapy (AIT) remain poorly understood. This study aimed to outline circulating B-cell signature, the underlying mechanism, and its association with clinical response to AIT in patients with AR. METHODS: IgD/CD27 and CD24/CD38 core gating systems were used to determine frequencies and phenotypes of B cells. Correlations between B cells, T cells, antigen-specific IgE, and disease severity in AR patients were investigated. Switched memory B cells were co-cultured with type 2 follicular helper T (Tfh2) cells and follicular regulatory T (Tfr) cells. Associations between B-cell subsets and clinical benefits of AIT were analyzed. RESULTS: Frequencies and absolute numbers of circulating memory B cells were increased in AR patients. CD23 expression on CD19+ CD20+ CD27+ IgD- switched memory B cells was significantly enhanced and positively correlated with antigen-specific IgE levels, symptom scores, and Tfh2/Tfr cell ratio in AR patients. Compared to those from healthy controls, Tfh2 cells from AR patients had a greater capacity to induce CD23 expression on switched memory B cells via IL-4, which was unable to be sufficiently suppressed by AR-associated Tfr cells with defective IL-10 expression. CD23 expression on switched memory B cells was downregulated after 12-month AIT, which positively associated with disease remission in AR patients. CONCLUSION: T-B cell interaction, bridged by CD23 expression particularly on switched memory B cells, may be involved in the disease pathogenesis and mechanism of AIT in patients with AR.

4.
J Neuroinflammation ; 17(1): 84, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171317

RESUMO

BACKGROUND: Studies suggest a role of the innate immune system, including the activity of neutrophils, in neurodegeneration related to Alzheimer's disease (AD), but prospective cognitive data remain lacking in humans. We aimed to investigate the predictive relationship between neutrophil-associated inflammatory proteins in peripheral blood and changes in memory and executive function over 1 year in patients with AD. METHODS: Participants with AD were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neutrophil gelatinase-associated lipocalin (NGAL), myeloperoxidase (MPO), interleukin-8 (IL-8), macrophage inflammatory protein-1 beta (MIP-1ß), and tumor necrosis factor (TNF) were assayed by luminex immunofluorescence multiplex assay at baseline. Confirmatory factor analysis was used to test an underlying neutrophil associated plasma inflammatory factor. Composite z-scores for memory and executive function were generated from multiple tests at baseline and at 1 year. A multiple linear regression model was used to investigate the association of the baseline inflammatory factor with changes in memory and executive function over 1 year. RESULTS: Among AD patients (n = 109, age = 74.8 ± 8.1, 42% women, Mini Mental State Examination [MMSE] = 23.6 ± 1.9), the neutrophil-related inflammatory proteins NGAL (λ = 0.595, p < .001), MPO (λ = 0.575, p < .001), IL-8 (λ = 0.525, p < .001), MIP-1ß (λ = 0.411, p = .008), and TNF (λ = 0.475, p < .001) were found to inform an underlying factor. Over 1 year, this inflammatory factor predicted a decline in executive function (ß = - 0.152, p = 0.015) but not memory (ß = 0.030, p = 0.577) in models controlling for demographics, brain atrophy, white matter hyperintensities, the ApoE ε4 allele, concomitant medications, and baseline cognitive performance. CONCLUSIONS: An inflammatory factor constructed from five neutrophil-related markers in peripheral blood predicted a decline in executive function over 1 year in people with mild AD.

5.
Nat Struct Mol Biol ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32203489

RESUMO

BRD4, a major tandem-bromodomain-containing transcription regulator, has two isoforms. The long isoform (BRD4L) has an extended C terminus that binds transcription cofactors, while the short isoform (BRD4S) lacks this C-terminal extension. Unlike BRD4L, the role of BRD4S in gene transcription remains unclear. Here, we report that, in human cancer cells, BRD4S forms nuclear puncta that possess liquid-like properties and that colocalize with BRD4L, MED1 and sites of histone H3 lysine 27 acetylation. BRD4 puncta are correlated with BRD4S but not BRD4L expression levels. BRD4S knockdown reduces BRD4S condensation, and ectopic expression promotes puncta formation and target gene transcription. BRD4S nuclear condensation is mediated by its intrinsically disordered regions and binding of its bromodomains to DNA and acetylated chromatin, respectively, and BRD4S phosphorylation diminishes BRD4 condensation. Our study illuminates a previously unappreciated role of BRD4S in organizing chromatin and transcription factors through phase separation to sustain gene transcription in chromatin for cancer cell proliferation.

7.
Transgenic Res ; 29(2): 199-213, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32078126

RESUMO

Despite great values in many applications, heavy chain-only antibodies (HcAbs) are naturally only produced in camelids and sharks, which are not easy to access and handle. Production of the type of antibodies in small laboratory animals would remarkably facilitate their applications. We previously reported a mouse line in which the CH1 exon of mouse γ1 was deleted that could express heavy chain-only IgG1 antibodies. However, these mice showed an extremely weak IgG1 response to specific antigens when immunized, and we could only achieve single VH domains with low affinity to antigens using these mice. One possibility is that the mouse germline VH repertoire was not sufficient to support the expression of functional heavy chain-only antibodies. In this study, we report the generation of a rat line in which the CH1 exon of the γ2a gene was removed and the γ1 and γ2b genes were silenced. Although the genetically modified rats expressed heavy chain-only IgG2a, they also exhibited a very weak IgG2a response to antigen immunization. Panning of a phage library constructed using IgG2a VH segments amplified from immunized rats identified antigen-specific single VH antibodies, which also exhibited much lower affinity than that of commercial mAbs. Together with our previous report, this study suggests that the simple genetic removal of the CH1 exon does not guarantee the successful expression of functional heavy chain-only antibodies.

8.
Cell Death Dis ; 11(1): 48, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969562

RESUMO

Oncolytic viruses have the potential to induce immunogenic cell death (ICD) that may provoke potent and long-lasting anti-cancer immunity. Here we aimed to characterize the ICD-inducing ability of wild-type Adenovirus (Ad), Semliki Forest virus (SFV) and Vaccinia virus (VV). We did so by investigating the cell death and immune-activating properties of virus-killed tumor cells. Ad-infection of tumor cells primarily activates autophagy, but also activate events of necroptotic and pyroptotic cell death. SFV infection on the other hand primarily activates immunogenic apoptosis while VV activates necroptosis. All viruses mediated lysis of tumor cells leading to the release of danger-associated molecular patterns, triggering of phagocytosis and maturation of dendritic cells (DCs). However, only SFV-infected tumor cells triggered significant T helper type 1 (Th1)-cytokine release by DCs and induced antigen-specific T-cell activation. Our results elucidate cell death processes activated upon Ad, SFV, and VV infection and their potential to induce T cell-mediated anti-tumor immune responses. This knowledge provides important insight for the choice and design of therapeutically successful virus-based immunotherapies.

9.
FASEB J ; 34(1): 30-40, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914661

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease caused by the dysfunction of immune system and consequently the destruction of insulin-producing ß cells. In past decades, numerous studies have uncovered that CD4+ T cell subsets are critical in the pathogenesis of T1D, manifesting that type 1 T helper (Th1) and Th17 cells are pathogenic, while regulatory T (Treg) cells and Th2 cells are protective. More recently, the pathogenic role of another subset, follicular helper T (Tfh) cells that essentially regulate germinal center (GC) formation and humoral responses, has also been demonstrated in T1D and many other autoimmune diseases. In this review, we summarize the evidence for the aberrant differentiation and function of Tfh cells in T1D, and also discuss the underlying mechanisms. A better understanding on the pathogenic role of Tfh cells in T1D will inspire the design of potential therapeutic strategies to target this subset in the future.

10.
Cancer Chemother Pharmacol ; 85(3): 509-515, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31654111

RESUMO

PURPOSE: To evaluate the predictive value of the in vitro chemosensitivity using ATP-TCA method to compare the clinical efficacy of patients with AML. METHODS: Bone marrow or peripheral blood samples were collected from 65 patients with AML, and the in vitro chemosensitivity of four drugs (cytarabine/idarubicin/decitabine/aclacinomycin) was measured by an ATP-tumor chemosensitivity assay. RESULTS: Aclacinomycin and cytarabine had the highest chemosensitivity rates (66.7%, 8/12 and 58.5%, 38/65, respectively), while idarubicin and decitabine had rates of 6.5% (3/46) and 0% (0/35), respectively. Complete remission (CR) was achieved in 66.2% (43/65) of patients, and there was a statistically significant correlation between CR and in vitro chemosensitivity for cytarabine (47.7% vs 18.5%, p = 0.002), but not for the anthracyclines (p = 0.950). In addition, three other factors significantly correlated with CR: disease status (p = 0.005), FLT3-ITD/TKD mutation (p = 0.003) and chemotherapy regimens (p = 0.004). Furthermore, multiple logistic regression analysis revealed that the sensitivity of cytarabine was one of the significant risk factors for CR [hazard ratio (HR) = 5.52; 95% confidence interval (CI) = 1.47-20.70; p = 0.011]. CONCLUSIONS: The in vitro chemosensitivity as tested by ATP-TCA demonstrated a significant correlation with CR for chemotherapy and can be a useful tool to optimize personalized treatments for patients with AML.

11.
Mol Cancer Ther ; 19(1): 221-230, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31548295

RESUMO

Mutations in genes encoding isocitrate dehydrogenases (IDH) 1 and 2 are common cancer-related genetic abnormalities. Malignancies with mutated IDHs exhibit similar pathogenesis, metabolic pattern, and resistance signature. However, an effective therapy against IDH1-mutated solid tumor remains unavailable. In this study, we showed that acquisition of IDH1 mutation results in the disruption of NADP+/NADPH balance and an increased demand for glutathione (GSH) metabolism. Moreover, the nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key protective role in IDH1-mutated cells by prompting GSH synthesis and reactive oxygen species scavenging. Pharmacologic inhibition of the Nrf2/GSH pathway via brusatol administration exhibited a potent tumor suppressive effect on IDH1-mutated cancer in vitro and in vivo Our findings highlight a possible therapeutic strategy that could be valuable for IDH1-mutated cancer treatment.

12.
Ann Rheum Dis ; 79(1): 141-149, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31537547

RESUMO

OBJECTIVES: Open-labelled clinical trials suggested that low-dose IL-2 might be effective in treatment of systemic lupus erythematosus (SLE). A double-blind and placebo-controlled trial is required to formally evaluate the safety and efficacy of low-dose IL-2 therapy. METHODS: A randomised, double-blind and placebo-controlled clinical trial was designed to treat 60 patients with active SLE. These patients received either IL-2 (n=30) or placebo (n=30) with standard treatment for 12 weeks, and were followed up for additional 12 weeks. IL-2 at a dose of 1 million IU or placebo was administered subcutaneously every other day for 2 weeks and followed by a 2-week break as one treatment cycle. The primary endpoint was the SLE Responder Index-4 (SRI-4) at week 12. The secondary endpoints were other clinical responses, safety and dynamics of immune cell subsets. RESULTS: At week 12, the SRI-4 response rates were 55.17% and 30.00% for IL-2 and placebo, respectively (p=0.052). At week 24, the SRI-4 response rate of IL-2 group was 65.52%, compared with 36.67% of the placebo group (p=0.027). The primary endpoint was not met at week 12. Low-dose IL-2 treatment resulted in 53.85% (7/13) complete remission in patients with lupus nephritis, compared with 16.67% (2/12) in the placebo group (p=0.036). No serious infection was observed in the IL-2 group, but two in placebo group. Besides expansion of regulatory T cells, low-dose IL-2 may also sustain cellular immunity with enhanced natural killer cells. CONCLUSIONS: Low-dose IL-2 might be effective and tolerated in treatment of SLE. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registries (NCT02465580 and NCT02932137).

13.
Meat Sci ; 160: 107958, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31669862

RESUMO

This study focused on sarcoplasmic and myofibrillar protein degradation and the formation of peptides with antioxidant activity by mixed starters (Lactobacillus plantarum CD101 and Staphylococcus simulans NJ201). Gel electrophoresis indicated that the mixed starters can hydrolyze both sarcoplasmic and myofibrillar proteins, and the concentration of peptides increased (P < .05). Compared with the control group, using mixed starters led to a significant increase (P < .05) in the DPPH radical scavenging activity, Fe2+ chelating activity, and ABTS radical scavenging activity of sarcoplasmic proteins, but demonstrated no significant difference in myofibrillar proteins. Two hydrophobic fractions (C2, C5) separated by RP-HPLC in the inoculation groups with sarcoplasmic proteins showed high DPPH radical scavenging activity (66.60%, 60.50%). Eighteen peptides were identified by LC-MS/MS, which mainly arose from triosephosphate isomerase, creatine kinase M-type, and glyceraldehyde-3-phosphate dehydrogenase. Hydrophobic amino acids accounted for a large proportion. Our results indicate that mixed starters affect proteolytic characterization and contribute to the formation of peptides with antioxidant capacity in sarcoplasmic proteins.


Assuntos
Lactobacillus plantarum/metabolismo , Produtos da Carne/microbiologia , Proteólise , Staphylococcus/metabolismo , Animais , Antioxidantes/química , Fermentação , Proteínas Musculares/metabolismo , Miofibrilas/metabolismo , Peptídeos/metabolismo , Suínos
14.
J Colloid Interface Sci ; 563: 318-327, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31884252

RESUMO

Molybdenum dioxides (MoO2) featuring low cost and high theoretical capacity endow them competitive anode materials for lithium-ion batteries (LIBs)/sodium-ion batteries (SIBs). However, the low electrical conductivity and severe volume expansion occurring during the ion insertion/extraction process hamper their practical application. Herein, a novel dual-annealing design has been developed for the synthesis of highly uniform MoO2 nanopopcorns decorated with nitrogen-doped carbon shell (MoO2/NC). Owing to the unique structural characteristics and vital amorphous NC component, the MoO2/NC nanopopcorn hybrid composite exhibits stabilized charge storage capacity of 1073 mAh g-1 after 200 cycles for LIBs, while 301 mAh g-1 after 500 cycles for SIBs at 0.5 A g-1. Furthermore, when the current density increases to 5 A g-1, the specific capacity could still maintain 630 mAh g-1 and 174 mAh g-1 for LIBs and SIBs, respectively, which disclose the outstanding rate capability of MoO2/NC nanopopcorn anode.

15.
Transl Oncol ; 13(2): 125-134, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31865175

RESUMO

The isocitrate dehydrogenase (IDH1/2) mutations are frequent genetic abnormalities in the majority of WHO grade II/III glioma and secondary GBM. IDH1-mutated (IDH1Mut) glioma exhibits distinctive patterns in cancer biology and metabolism. In the present study, we showed that bone morphogenetic proteins (BMP4) are significantly upregulated in IDH1Mut glioma. Further, we demonstrated that cancer-associated BMP4 is secreted to tumor microenvironment, which enhances the tumor migration and invasion through an autocrine manner. Mechanistically, BMP4 activates its receptor and concomitant SMAD1/5/8 signaling, which potentiates Wnt/ß-catenin signaling by enhancing Frizzled receptor expression. LDN-193189, a selective BMP receptor inhibitor, prolonged the overall survival of mice bearing IDH1-mutated intracranial xenografts by limiting BMP/catenin signaling. These findings demonstrate the pivotal role of BMP4 on tumor aggressiveness in IDH1Mut gliomas, suggesting a possible therapeutic strategy for this type of malignancy.

16.
Dalton Trans ; 48(44): 16776-16785, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31674607

RESUMO

A novel metal-organic framework with the formula [Zn3(DDB)(DPE)]·H2O (1) (H5DDB = 3,5-di(2',4'-dicarboxylphenyl)benzoic acid and DPE = 1,2-di(4-pyridyl)ethylene) has been solvothermally synthesized by employing a rigid carboxylate ligand H5DDB to assemble with Zn(ii) ions in the presence of a flexible bis(pyridyl) linker DPE. The Zn-MOF is a 3D framework with six-nuclear clusters and possesses remarkable water stability and pH stability. Interestingly, complex 1 can sensitively and selectively sense Fe(iii), Cr(iii), Cr(vi), Mn(vii) and the pesticide 2,6-Dich-4-NA with low detection limits in aqueous solution. Moreover, complex 1 also exhibits selectivity for 2,6-Dich-4-NA detection in real samples including carrot, grape and nectarine extracts, and its detection ability is almost unchanged in the presence of the surfactant sodium dodecyl sulfate (SDS). The possible mechanisms of luminescence quenching have been explained by the weak affinity of nitrogen atoms, resonance energy transfer, and photoinduced electron transfer. To our knowledge, this is the first example of a MOF-based multiresponsive fluorescent probe for the simultaneous detection of Fe(iii), Cr(iii/vi), Mn(vii) and the pesticide 2,6-Dich-4-NA in aqueous solution.

17.
J Immunol Res ; 2019: 7616509, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737688
18.
Sci Immunol ; 4(41)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31732518

RESUMO

Mucosal-associated invariant T (MAIT) cells are activated in a TCR-dependent manner by antigens derived from the riboflavin synthesis pathway, including 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), bound to MHC-related protein-1 (MR1). However, MAIT cell activation in vivo has not been studied in detail. Here, we have found and characterized additional molecular signals required for optimal activation and expansion of MAIT cells after pulmonary Legionella or Salmonella infection in mice. We show that either bone marrow-derived APCs or non-bone marrow-derived cells can activate MAIT cells in vivo, depending on the pathogen. Optimal MAIT cell activation in vivo requires signaling through the inducible T cell costimulator (ICOS), which is highly expressed on MAIT cells. Subsequent expansion and maintenance of MAIT-17/1-type responses are dependent on IL-23. Vaccination with IL-23 plus 5-OP-RU augments MAIT cell-mediated control of pulmonary Legionella infection. These findings reveal cellular and molecular targets for manipulating MAIT cell function under physiological conditions.

20.
Neurology ; 93(19): e1807-e1819, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31575706

RESUMO

OBJECTIVE: To determine if APOE ε4 influences the association between white matter hyperintensities (WMH) and cognitive impairment in Alzheimer disease (AD) and dementia with Lewy bodies (DLB). METHODS: A total of 289 patients (AD = 239; DLB = 50) underwent volumetric MRI, neuropsychological testing, and APOE ε4 genotyping. Total WMH volumes were quantified. Neuropsychological test scores were included in a confirmatory factor analysis to identify cognitive domains encompassing attention/executive functions, learning/memory, and language, and factor scores for each domain were calculated per participant. After testing interactions between WMH and APOE ε4 in the full sample, we tested associations of WMH with factor scores using linear regression models in APOE ε4 carriers (n = 167) and noncarriers (n = 122). We hypothesized that greater WMH volume would relate to worse cognition more strongly in APOE ε4 carriers. Findings were replicated in 198 patients with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI-I), and estimates from both samples were meta-analyzed. RESULTS: A significant interaction was observed between WMH and APOE ε4 for language, but not for memory or executive functions. Separate analyses in APOE ε4 carriers and noncarriers showed that greater WMH volume was associated with worse attention/executive functions, learning/memory, and language in APOE ε4 carriers only. In ADNI-I, greater WMH burden was associated with worse attention/executive functions and language in APOE ε4 carriers only. No significant associations were observed in noncarriers. Meta-analyses showed that greater WMH volume was associated with worse performance on all cognitive domains in APOE ε4 carriers only. CONCLUSION: APOE ε4 may influence the association between WMH and cognitive performance in AD and DLB.


Assuntos
Doença de Alzheimer/psicologia , Apolipoproteína E4/genética , Disfunção Cognitiva/psicologia , Doença por Corpos de Lewy/psicologia , Substância Branca/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Atenção , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Função Executiva , Análise Fatorial , Feminino , Humanos , Linguagem , Aprendizagem , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/genética , Modelos Lineares , Imagem por Ressonância Magnética , Masculino , Memória , Pessoa de Meia-Idade , Testes Neuropsicológicos
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