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1.
Sci Transl Med ; 13(587)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790024

RESUMO

The functional state of T cells is a key determinant for effective antitumor immunity and immunotherapy. Cellular metabolism, including lipid metabolism, controls T cell differentiation, survival, and effector functions. Here, we report that development of T cell senescence driven by both malignant tumor cells and regulatory T cells is a general feature in cancers. Senescent T cells have active glucose metabolism but exhibit unbalanced lipid metabolism. This unbalanced lipid metabolism results in changes of expression of lipid metabolic enzymes, which, in turn, alters lipid species and accumulation of lipid droplets in T cells. Tumor cells and Treg cells drove elevated expression of group IVA phospholipase A2, which, in turn, was responsible for the altered lipid metabolism and senescence induction observed in T cells. Mitogen-activated protein kinase signaling and signal transducer and activator of transcription signaling coordinately control lipid metabolism and group IVA phospholipase A2 activity in responder T cells during T cell senescence. Inhibition of group IVA phospholipase A2 reprogrammed effector T cell lipid metabolism, prevented T cell senescence in vitro, and enhanced antitumor immunity and immunotherapy efficacy in mouse models of melanoma and breast cancer in vivo. Together, these findings identify mechanistic links between T cell senescence and regulation of lipid metabolism in the tumor microenvironment and provide a new target for tumor immunotherapy.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33807669

RESUMO

(1) Background: Numerous studies suggest strong associations between childhood maltreatment and nonsuicidal self-injury (NSSI); this is also true for the roles of dopaminergic genes in the etiology of some psychopathologies related to NSSI. Investigating the interactions of environments and genes is important in order to better understand the etiology of NSSI. (2) Methods: Within a sample of 269 Chinese male adolescents (Mage = 14.72, SD = 0.92), childhood maltreatment and NSSI were evaluated, and saliva samples were collected for MAOA T941G and COMT Val158Met polymorphism analyses. (3) Results: The results revealed no primary effects attributable to MAOA T941G and COMT Val158Met polymorphism on NSSI. However, there was a significant three-way interaction between MAOA, COMT, and child abuse (ß = -0.34, p < 0.01) in adolescent NSSI. Except for carriers of the T allele of MAOA and the Met allele of COMT, all studied male adolescents displayed higher NSSI scores when exposed to a higher level of child abuse. A similar three-way interaction was not observed in the case of child neglect. (4) Conclusions: The results indicate that the MAOA gene and COMT gene play moderating roles in the association between child abuse and NSSI of male adolescents and suggest the polygenic underpinnings of NSSI.

3.
J Stud Alcohol Drugs ; 82(2): 204-213, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33823967

RESUMO

OBJECTIVE: An online training in responsible marijuana vendor (RMV) practices was evaluated for effects on compliance with ID checking regulations. METHOD: A random sample of state-licensed recreational marijuana stores (n = 175) in Colorado and Washington State was selected in 2016-2017 and was enrolled in a randomized pretest-posttest controlled design. After baseline assessment, 75 stores were randomly assigned to a usual and customary training control group, stratified by state and region. The remaining stores (n = 100) were invited to use the RMV training. Stores were posttested at 3 and 9 months postrandomization. The primary outcome was refusal of sale measured with pseudo-underage patrons who attempted to enter stores and purchase cannabis without a state-approved ID. RESULTS: There was no difference by treatment group in refusal of pseudo-underage patron buyers (baseline: 92.5% intervention vs. 94.7% control; 3-month posttest 94.8% vs. 97.5%; 9-month posttest 97.5% vs. 97.1%, p = .286 [one tailed, adjusted for covariates]). The use of training increased refusals at store entry (trained: 65.9% baseline 82.5%, 3 months 79.9%, 9 months; not trained: 82.6%, 83.1%, 84.5%, p = .020 [two tailed, adjusted for covariates]). This difference was especially evident in Washington State (trained: 40.3%, 65.1%, 60.4%; not trained: 57.9%, 68.5%, 72.3%) but not in Colorado (trained: 95.2%, 101.0%, 101.4; not trained: 95.7%, 98.6%, 99.2%, p = .033 [two tailed, adjusted for covariates]). CONCLUSIONS: When used by store personnel, online RMV training increased refusal of buyers who appeared young and did not provide a state-approved ID. However, it did not improve refusal rates overall. Stores that had lower refusals at baseline and used the training may have benefited from it.

4.
Am J Hematol ; 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33819355

RESUMO

MYD88L265P and CXCR4S338X variants are highly prevalent and impact disease presentation, prognosis, and/or treatment outcome in Waldenstrom's Macroglobulinemia (WM). The use of bone marrow (BM) aspirate represents the current "gold standard" for molecular testing in WM. Although these variants are identified in peripheral blood (PB), the diagnostic yield in PB is inferior to BM, particularly for previously treated patients. Tumor enrichment can significantly improve testing sensitivity, but is not feasible in most clinical laboratories. Recent studies have demonstrated the feasibility of identifying MYD88 and CXCR4 mutations using cell-free DNA (cfDNA) from the plasma of WM patients. We therefore prospectively collected matched BM and PB samples from 28 consecutive WM patients. Overall, five different tissue fractions were isolated for analysis: CD19-selected BM, unselected BM, CD19-selected PB, unselected PB, and cfDNA. Quantitative allele-specific polymerase chain reaction assays for MYD88L265P and CXCR4S338X mutations were performed for each tissue fraction, and findings benchmarked against CD19-selected BM. Both MYD88L265P and CXCR4S338X were identified with high sensitivity and specificity in cfDNA derived from the plasma of WM patients, including previously treated patients. The use of cfDNA represents a non-invasive, convenient, and potentially cost-effective method for genotyping patients with WM. This article is protected by copyright. All rights reserved.

5.
Biomed Chromatogr ; : e5133, 2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33811357

RESUMO

The overall chemical composition of Bupleurum marginatum var. stenophyllum and B. chinense DC was compared in this study. Metabolites were identified using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Multivariate statistical analysis techniques such as principal component analysis (PCA) were used to conduct metabonomics analysis and study the correlation between different components. PCA results showed a clear distinction among medicinal materials of different origins and divided them into different categories, consistent with the results of hierarchical cluster analysis (HCA). Both partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA) showed that the two materials could be distinguished clearly. Using PLS-DA and OPLS-DA combined with the S-plot and a VIP score >1, 24 differential metabolites were screened and identified; all the metabolites were triterpenoid saponins. In addition, SPSS 25.0 and Metabo Analyst 4.0 were used to analyze significant differences in the relative contents of different compounds in the two materials. This study has successfully provided not only a new direction for research based on the chemical substances identified and the quality evaluation of Bupleuri Radix but also a better theoretical basis for the expansion of medicinal sources and their clinical application.

6.
J Ethnopharmacol ; : 114103, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33836259

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Zuojin Pill (ZJP) has been a classic prescription for the treatment of gastrointestinal diseases in China since ancient times. But its effect on non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric injury (GI) is still uncharted. AIM OF THE STUDY: This study aims to investigate the therapeutic effect and molecular mechanism of ZJP on indomethacin (IDO) induced gastric injury. MATERIALS AND METHODS: GI was induced in rat by oral administration of 5mg/kg IDO. Then the rats were treated with ZJP (1.26, 2.52, 5.04g/kg, ig). The changes of food intake, body weight, gastric pH and general state observation were carried out to determine the improvement of ZJP in IDO-induced GI: HE staining and AB-PAS staining was analyzed to characterize the thickness of gastric mucosa and micro mucosal injury; in order to elucidate the effect of ZJP on IDO-induced inflammatory injury, the inflammatory infiltration of gastric tissue was observed by MPO immunohistochemical method, and the contents of TNF-α, IL-6 and IL-10 were measured. Furthermore, the regulatory mechanism of ZJP in treating IDO-induced GI was predicted with the help of network pharmacology, and the expression levels of key proteins ERK, p-ERK, P38, p-P38, JNK, p-JNK were determined to elucidate the molecular mechanism of ZJP. RESULTS: Current data strongly demonstrated that ZJP alleviated food intake reduction, weight loss and gastric injury caused by IDO and made gastric pH and mucosal thickness return to normal. In addition, ZJP could reduce the level of MPO to alleviate the inflammatory infiltration of gastric tissue. Simultaneously, ZJP could down regulate the expression of TNF-α and IL-6 and up regulate the expression of IL-10 to reduce the damage caused by inflammatory, and create a healing environment. Furthermore, ZJP could significantly inhibit the phosphorylation of ERK, p38 and JNK, which leaded to the increase of inflammatory factors and the damage of gastric mucosa. CONCLUSION: ZJP improved local inflammation by inhibiting MAPK signaling pathway, and had a good therapeutic effect on IDO-induced GI. This study has reference significance for the study of ZJP in the prevention and treatment of NSAID induced gastric injury. In addition, ZJP may be a new treatment option for the prevention and treatment of NSAID induced gastric disease.

7.
Neurol Sci ; 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33837876

RESUMO

Glucocerebrosidase (GBA) gene has been proved to be a risk factor for the development of Parkinson's disease (PD). However, the gender effect in the prevalence of GBA-associated PD (GBA-PD) is still controversial. And there is no conclusion whether the age at onset (AAO) of PD is different between carriers and non-carriers of GBA. To clarify the association between gender and AAO in GBA-PD, we conducted a systematic review and meta-analysis. PubMed, Web of Science, and Embase were retrieved to obtain potentially related studies. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine the association between gender and GBA-PD. And the weighted mean difference (WMD) with 95% CIs was employed to assess the difference of AAO between carriers and non-carriers of GBA. A total of twenty-eight studies involving 16,488 PD patients were included in this meta-analysis. The results showed the prevalence of female patients was higher in GBA-PD [OR: 1.19, (95% CI, 1.07-1.32), P = 0.001]. Meanwhile, GBA carriers had younger age at PD onset than GBA non-carriers [WMD: 2.87, (95% CI, 2.48-3.27), P < 0.001]. Results of subgroup analysis showed the prevalence of women in GBA-PD was higher than men in North American and European PD patients, while the gender difference was not significant in other areas around the world, suggesting an ethnic specificity of gender effect for GBA-PD. Our results indicate the higher female prevalence with ethnic specificity and younger AAO of GBA carriers in GBA-PD.

8.
BMC Genomics ; 22(1): 202, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33752589

RESUMO

BACKGROUND: Cotton fiber is a model system for studying plant cell development. At present, the functions of many transcription factors in cotton fiber development have been elucidated, however, the roles of auxin response factor (ARF) genes in cotton fiber development need be further explored. RESULTS: Here, we identify auxin response factor (ARF) genes in three cotton species: the tetraploid upland cotton G. hirsutum, which has 73 ARF genes, and its putative extent parental diploids G. arboreum and G. raimondii, which have 36 and 35 ARFs, respectively. Ka and Ks analyses revealed that in G. hirsutum ARF genes have undergone asymmetric evolution in the two subgenomes. The cotton ARFs can be classified into four phylogenetic clades and are actively expressed in young tissues. We demonstrate that GhARF2b, a homolog of the Arabidopsis AtARF2, was preferentially expressed in developing ovules and fibers. Overexpression of GhARF2b by a fiber specific promoter inhibited fiber cell elongation but promoted initiation and, conversely, its downregulation by RNAi resulted in fewer but longer fiber. We show that GhARF2b directly interacts with GhHOX3 and represses the transcriptional activity of GhHOX3 on target genes. CONCLUSION: Our results uncover an important role of the ARF factor in modulating cotton fiber development at the early stage.

9.
J Genet ; 1002021.
Artigo em Inglês | MEDLINE | ID: mdl-33764335

RESUMO

AGLl9 is an important regulator for flowering in plants and critical in controlling the morphogenesis of flower organs. The fulllength cDNAs of AGL19in conventional Lonicera macranthoides (Lm-AGL19) and the mutant 'Xianglei' cultivar (Lm-XL-AGL19) were obtained using rapid amplification of cDNA ends and the expression vectors for Lm-XL-AGL19were constructed to investigate the roles of AGL19 in the 'Xianglei' cultivar. Lm-AGL19 (GenBank: MK419948) and Lm-XL-AGL19 (GenBank: MK419948) were isolated from the conventional variety and 'Xianglei' cultivar of L. macranthoides, respectively. Lm-AGL19 is 1274 bp in length, whereas Lm-XL-AGL19 is 1264-bp long, and both include a 654 bp open reading frame, encoding 217 amino acids, which has a highly conserved MADS_MEF2_like domain and a moderately conserved K-box domain, belonging to the type II MADS-box family of genes. Quantitative real-time polymerase chain reaction indicated that the expression levels of these genes at different flowering stages were significantly different, and that the genes were also expressed in stems and leaves. Lm-XL-AGL19 is underexpressed at flowering period 5 that the key time node for corolla expansion and nonexpansion, while LM-AGL19 is overexpressed during this flowering period. AGL19 was speculated to be a functional gene causing different phenotypes in the two L. macranthoides varieties. The successfully constructed plant expression vector provides an experimental reference for further research on the function of this gene and the basis for the excellent phenotype of L. macranthoides 'Xianglei'.

10.
Food Chem ; 353: 129464, 2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33740511

RESUMO

The magnetic molecular imprinting polymers nanoparticles (MMIPs NPs) for the extraction of norfloxacin (NOR) were prepared by self-polymerization of dopamine onto the surface of (3-Aminopropyl)triethoxysilane (APTES)-modified Fe3O4 NPs. The MMIPs NPs were characterized by FT-IR spectroscopy, XRD, VSM and TEM. The characterization results show that the MMIPs NPs possess superparamagnetic characteristic with the saturated magnetization value of 38.6 emu/g, and the average particle size of about 14.3 nm. Furthermore, the adsorption performance of the MMIPs NPs was evaluated by the static, dynamic, selective adsorption and reusability experiments. The adsorption capacity of MMINs NPs for NOR is 14.2 mg/g with an imprinted factor of 2.1. About 82.4-102.4% of the added NOR (20, 40, 60 µg/mL) were recovered from fortified milk samples with MMIPs NPs as sorbent. Moreover, the MMIPs NPs can be reused for at least six times.

11.
Oxid Med Cell Longev ; 2021: 1457089, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777312

RESUMO

Reactive oxygen species (ROS) production by activation of microglia is considered to be a major cause of neuronal dysfunction, which can lead to damage and death through direct oxidative damage to neuronal macromolecules or derangement of neuronal redox signaling circuits. BAP31, an integral ER membrane protein, has been defined as a regulatory molecule in the CNS. Our latest studies have found that BAP31 deficiency leads to activation of microglia. In this study, we discovered that BAP31 deficiency upregulated LPS-induced superoxide anion production in BV2 cells and mice by upregulating the expression level of p22phox and by inhibiting the activation of Nrf2-HO-1 signaling. Knockdown of p22phox/keap1 or use of an NADPH oxidase inhibitor (apocynin) reversed the production of superoxide anion and inflammatory cytokines, which then reduced neuronal damage and death in vitro and in vivo. These results suggest that BAP31 deficiency contributes to microglia-related superoxide anion production and neuroinflammation through p22phox and keap1. Furthermore, the excess superoxide anion cooperated with inflammatory cytokines to induce the damage and death of neurons. Thus, we determined that BAP31 is an important regulator in superoxide anion production and neuroinflammation, and the downstream regulators or agonists of BAP31 could therefore be considered as potential therapeutic targets in microglial-related superoxide anion production and neuroinflammation.

12.
BMC Cardiovasc Disord ; 21(1): 148, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33757438

RESUMO

BACKGROUND: In China, there has been a precipitous increase in the number of percutaneous coronary interventions (PCI) conducted. We sought to characterize the clinical and psychosocial trajectory of PCI patients from the time of procedure through 6 months post, and correlates of adverse cardiovascular events (ACEs). METHODS: In this prospective, observational study, patients from 2 hospitals in Shanghai, China were assessed. At follow-up visits at 1, 3 and 6 months post-PCI, clinical indicators were again extracted from patients' clinical records, including ACEs, and they completed validated surveys assessing self-management, as well as psychosocial indicators (Hospital Anxiety and Depression Scale; Pittsburgh Sleep Quality Index; quality of life [QoL]: SF-12, Seattle Angina Questionnaire [SAQ]). Repeated measures analysis of variance, adjusted for Barthel index and PCI indication, was used to assess change over time in risk factors and psychosocial indicators. Logistic regression was used to explore correlates of ACEs. RESULTS: 610 participants (mean age = 63.3; n = 150, 18.2% female) were recruited, of which 491 (80.5%) were retained at 6 months. 82 (16.7%) had an ACE at any time point, including most commonly angina and stroke (only 1 death). Clinical indicators such as blood pressure (p < 0.031 for both), symptom burden (p < .01 on all subscales) and QoL (p < 0.001 for both, but started quite low) improved over 6 months. Anxiety and depressive symptoms were above threshold, and the latter worsened over time (p < 0.001). With adjustment for age and indication, patients with any ACEs had higher sleep latency (odds ratio [OR] = 1.48; 95% confidence interval [CI] = 1.03-2.10]), and depressive symptoms (OR = 1.20; 95% CI = 1.02-1.41), but lower anxiety (OR = 0.79; 95% CI = 0.67-0.93) compared to those without. CONCLUSION: Centers may wish to re-visit patient selection criteria and processes for PCI, as well as implement mental health screening and treatment protocols, as can be achieved through cardiac rehabilitation, given how hazardous psychosocial distress is in this population.

13.
Artigo em Inglês | MEDLINE | ID: mdl-33733408

RESUMO

Water erosion is one of the main types of soil degradation, but few quantitative estimates have been done in the soil erosion intensity grades of different landscape scaling characteristics in a large-scale ecological restoration watershed. This study comparatively illustrates the utility of high-resolution data and geospatial technique, particularly the GIS-based RUSLE model, for an improved understanding of the spatial patterns of soil erosion under different land use types, geomorphological styles, vegetational regionalizations, and geographical zonings, aiming to promote ecological sustainable watershed management in practice. Results indicate the following:(i) The soil erosion intensity grade showed an overall decreasing trend from northwest to southeast in the Jinghe River Watershed. The percentages of intense erosion and extremely intense erosion in different land use types in 2015 were significantly lower than that in 2000 except middle- and low-coverage grasslands because of the effective implementation of "Grain for Green" project. e.g., the percentage of extremely intense erosion in dry land decreased from 41.72% in 2000 to 8.99% in 2015.(ii) The mid-elevation loessial beams and hills and mid-elevation loessial tableland were both the major sources of intense erosion and extremely intense erosion, with the contribution ratio of 41.89 and 53.94% and 35.79 and 20.83% in 2000 and 44.45 and 48.99% and 36.88 and 18.72% in 2015, respectively.(iii) The intense, extremely intense and severe erosion in the temperate typical grassland subzone accounted for 32.62, 44.47, and 9.6% in 2000 and 36.74, 40.7, and 8.1% in 2015, respectively. There were no severe and extremely intense erosion in the deciduous oak forest subzone of northern and southern warm temperate. (iv) The intense, extremely intense, and severe erosion of the loessial wide valley hills accounted for 32.19, 45.27, and 8.92% in 2000 and 36.32, 41.42, and 7.48% in 2015. The intense and extremely intense erosion of the loessial tableland accounted for 40.58 and 16.02% in 2000 and 40.57 and 14.27% in 2015. More importantly, land use types can be applied to the design and implementation of a development scheme more reliably than other landscapes because the land use system is a more scientific and fine classification based on topography, soils, and vegetation correlated with geology, geomorphology, and climate. The knowledge on the fine landscape scale will be useful for comprehensive watershed management by soil scientists, agronomists, environmental scientists, land managers, and policymakers.

14.
Artigo em Inglês | MEDLINE | ID: mdl-33652641

RESUMO

Ethnic minority college students in China are Chinese students who migrate from ethnic minority-dominant areas to Han-dominant areas to attend college. Acculturative stress would lead to maladjustments for ethnic minority college students in China, such as low levels of life satisfaction. To help improve the life satisfaction of these students, this study adopted resilience theory to explore the beneficial effects of hope and social support and their influencing mechanisms. The participants included 362 ethnic minority college students in Beijing, China, and a questionnaire method was used. The results indicated that Han social support had a promotive effect on life satisfaction, while hope did not have a promotive effect on life satisfaction. Moreover, Han social support moderated the relationship between hope and life satisfaction. Specifically, the effect of hope on life satisfaction was stronger under the condition of a higher level of Han social support compared with those under a lower level of Han social support. In conclusion, Han social support can play a promotive effect individually, while hope only affected life satisfaction when a high level of Han social support existed. Han social support should be strengthened to improve the life satisfaction among ethnic minority college students in China.

15.
J Immunother Cancer ; 9(3)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33653799

RESUMO

BACKGROUND: Current immunotherapies including checkpoint blockade therapy have limited success rates in certain types of cancers. Identification of alternative checkpoint molecules for the development of effective strategies for tumor immunotherapy is urgently needed. Immunoglobulin-like transcript 4 (ILT4) is an immunosuppressive molecule expressed in both myeloid innate cells and malignant tumor cells. However, the role of tumor-derived ILT4 in regulating cancer biology and tumor immunity remains unclear. METHODS: ILT4 expression in tumor cells and patient samples was determined by real-time PCR, flow cytometry, and immunohistochemistry. T cell senescence induced by tumor was evaluated using multiple markers and assays. Moreover, metabolic enzyme and signaling molecule expression and lipid droplets in tumor cells were determined using real-time PCR, western blot and oil red O staining, respectively. Loss-of-function and gain-of-function strategies were used to identify the causative role of ILT4 in tumor-induced T cell senescence. In addition, breast cancer and melanoma mouse tumor models were performed to demonstrate the role of ILT4 as a checkpoint molecule for tumor immunotherapy. RESULTS: We reported that ILT4 is highly expressed in human tumor cells and tissues, which is negatively associated with clinical outcomes. Furthermore, tumor-derived ILT4/PIR-B (ILT4 ortholog in mouse) is directly involved in induction of cell senescence in naïve/effector T cells mediated by tumor cells in vitro and in vivo. Mechanistically, ILT4/PIR-B increases fatty acid synthesis and lipid accumulation in tumor cells via activation of MAPK ERK1/2 signaling, resulting in promotion of tumor growth and progression, and induction of effector T cell senescence. In addition, blocking tumor-derived PIR-B can reprogram tumor metabolism, prevent senescence development in tumor-specific T cells, and enhance antitumor immunity in both breast cancer and melanoma mouse models. CONCLUSIONS: These studies identify a novel mechanism responsible for ILT4-mediated immune suppression in the tumor microenvironment, and prove a novel concept of ILT4 as a critical checkpoint molecule for tumor immunotherapy.

16.
Prog Neurobiol ; : 102032, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33716161

RESUMO

ApoE4, an apolipoprotein implicated in cholesterol transport and amyloid-ß (Aß) metabolism, is a major genetic risk determinant for Alzheimer's Disease (AD) and drives its pathogenesis via Aß-dependent and -independent pathways. C/EBPß, a proinflammatory cytokines-activated transcription factor, is upregulated in AD and mediates cytokines and δ-secretase expression. However, how ApoE4 contributes to AD pathogenesis remains incompletely understood. Here we show that ApoE4 and 27-hydroxycholesterol (27-OHC) co-activate C/EBPß/δ-secretase signaling in neurons, mediating AD pathogenesis, and this effect is dependent on neuronal secreted Aß and inflammatory cytokines. Inhibition of cholesterol metabolism with lovastatin diminishes neuronal ApoE4's stimulatory effects. Furthermore, ApoE4 and 27-OHC also mediate lysosomal δ-secretase leakage, activation, secretion and endocytosis. Notably, 27-OHC strongly activates C/EBPß/δ-secretase pathway in human ApoE4-TR mice and triggers AD pathologies and cognitive deficits, which is blocked by C/EBPß depletion. Hence, our findings demonstrate that ApoE4 and 27-OHC additively trigger AD pathogenesis via activating C/EBPß/δ-secretase pathway. Lowering cholesterol levels with statins should benefit the ApoE4 AD carriers.

17.
Artigo em Inglês | MEDLINE | ID: mdl-33676007

RESUMO

STUDY OBJECTIVE: To assess whether a full enhanced recovery after surgery (ERAS) program can further improve perioperative outcomes among patients undergoing gynecologic laparoscopic procedures relative to those receiving limited ERAS management. DESIGN: Randomized controlled trial SETTING: A tertiary hospital, China: December 2018 to October 2019 PATIENTS: A total of 144 women scheduled for simple elective gynecologic laparoscopic surgery. INTERVENTIONS: The participants were randomized into two groups: full ERAS intervention or limited ERAS management (without preoperative carbohydrate loading or total intravenous anesthesia or opiate-sparing multimodal analgesia). MEASUREMENTS AND MAIN RESULTS: The primary outcome was postoperative length of stay (LOS), and the secondary outcomes included postoperative pain, time to postoperative milestones, morbidity, and in-hospital cost. Postoperative LOS for the full ERAS program showed a 1-day reduction in comparison to the limited ERAS group (median of 1.0 day versus 2.0 days, respectively; P = .001). Multivariate regression analysis identified preoperative carbohydrate loading and opioid-sparing analgesia as the independent factors for discharging on postoperative day (POD) 1. Patients in the full ERAS program reported less pain within 72 hours after surgery and had a lower narcotic consumption rate compared with those in the limited ERAS management. They also enjoyed better and faster recovery as demonstrated by the QoR-15 scale on POD 3: 137.0 (interquartile range, 126.3-141.0) for full ERAS program versus 130.0 (23.5-139.0) for limited ERAS management, respectively (P = .030). There were no significant differences between groups regarding postoperative 30-day morbidity, readmission rate, or in-hospital cost. CONCLUSION: The addition of full ERAS management can further reduce postoperative length of stay and improve patients' quality of life after laparoscopic surgery for gynecologic diseases.

18.
Br J Haematol ; 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33713429

RESUMO

CXCR4 mutations impact disease presentation and treatment outcomes in Waldenström macroglobulinaemia (WM). Non-uniform testing for CXCR4 mutations may account for discordant findings in WM clinical trials. We compared two approaches used in these trials for detection of the most common CXCR4 (S338X) variant: targeted next-generation sequencing (NGS) using unselected bone marrow (BM) samples, and combined allele-specific polymerase chain reaction (AS-PCR) and Sanger sequencing with unselected and CD19-selected BM samples. Our findings showed that targeted NGS frequently yielded false-negative results. Both CD19 selection and AS-PCR markedly improved detection of CXCR4S338X mutations. Sensitivity was adversely impacted by low BM involvement and CXCR4 mutation clonality.

19.
Life Sci ; 274: 119249, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33652034

RESUMO

BACKGROUND: Accumulating evidence has reported the role of microRNA (miR) on atherosclerosis (AS), while it is unclear about the relationship between microRNA-125b-5p (miR-125b-5p) and AS. Thus, the object of this study was to investigate the impact of exosomal miR-125b-5p targeting mitogen-activated protein 4 kinase 4 (Map4k4) on AS plaque formation. METHODS: The AS model was established using a high fat diet in ApoE-/- mice. Mouse bone marrow-derived mesenchymal stem cells (BMSCs) were selected and BMSC-exosomes (BMSC-EXO) were extracted and then identified. The targeted relationship between miR-125b-5p and Map4k4 was tested. BMSC-EXO were modified with miR-125b-5p- and Map4k4-related sequences to interfere with AS mice. MiR-125b-5p and Map4k4 expression in AS tissues were tested. The inflammation-related indices, blood lipid, plaque area, apoptosis index, MMP-9 and α-SMA expression in mice with AS were measured. RESULTS: BMSCs and BMSC-EXO were successfully isolated. MiR-125b-5p was down-regulated and Map4k4 was up-regulated in aorta tissues from ApoE-/- mice after AS modeling, verses those from C57BL/6 mice without modeling. MiR-125b-5p targeted Map4k4. BMSC-EXO increased miR-125b-5p expression and decreased Map4k4 expression. BMSC-EXO/up-regulated miR-125b-5p and down-regulated Map4k4 in exosomes decreased inflammatory reaction, blood lipid, plaque area, MMP-9 expression and increased α-SMA expression, as well as inhibited apoptosis index of AS mice. CONCLUSION: Functional studies revealed that exosomal miR-125b-5p from BMSCs suppresses atherosclerotic plaque formation via inhibiting Map4k4 expression.

20.
Commun Biol ; 4(1): 265, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33649493

RESUMO

Large numbers of cells are generally required for quantitative global proteome profiling due to surface adsorption losses associated with sample processing. Such bulk measurement obscures important cell-to-cell variability (cell heterogeneity) and makes proteomic profiling impossible for rare cell populations (e.g., circulating tumor cells (CTCs)). Here we report a surfactant-assisted one-pot sample preparation coupled with mass spectrometry (MS) method termed SOP-MS for label-free global single-cell proteomics. SOP-MS capitalizes on the combination of a MS-compatible nonionic surfactant, n-Dodecyl-ß-D-maltoside, and hydrophobic surface-based low-bind tubes or multi-well plates for 'all-in-one' one-pot sample preparation. This 'all-in-one' method including elimination of all sample transfer steps maximally reduces surface adsorption losses for effective processing of single cells, thus improving detection sensitivity for single-cell proteomics. This method allows convenient label-free quantification of hundreds of proteins from single human cells and ~1200 proteins from small tissue sections (close to ~20 cells). When applied to a patient CTC-derived xenograft (PCDX) model at the single-cell resolution, SOP-MS can reveal distinct protein signatures between primary tumor cells and early metastatic lung cells, which are related to the selection pressure of anti-tumor immunity during breast cancer metastasis. The approach paves the way for routine, precise, quantitative single-cell proteomics.

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