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1.
Cancer Epidemiol ; 65: 101683, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32045872

RESUMO

BACKGROUND: Although a number of previous studies have noted the association between body mass index (BMI) and upper gastrointestinal (UGI) cancer risk, little evidence exists in the Chinese esophageal squamous dysplasia population. This prospective study investigated the association between BMI and UGI cancer risk in the Linxian Dysplasia Nutrition Intervention Trial (NIT) cohort. METHODS: A total of 3298 participants were included in the final analysis. Asian-specific BMI cut-offs were used to define BMI subgroups: underweight <18.5 kg/m2, normal ≥18.5 to <24 kg/m2 and overweight or obese ≥24 kg/m2. Hazard ratios (HRs) and 95 % confidence intervals (95 %CIs) were estimated using the Cox proportional hazard model. RESULTS: During over 30 years of follow-up we identified 654 incident esophageal squamous-cell carcinoma (ESCC) cases and 434 gastric cancer cases which included 88 gastric non-cardia carcinoma (GNCC) and 346 gastric cardia carcinoma (GCC) cases. Relative to normal weight, overweight or obesity were associated with a significantly reduced risk of ESCC (HR 0.69, 95 %CI 0.48-0.98) after multivariate adjustment, including age at baseline, gender, smoking, drinking, family history of cancer, education and consumption of fresh fruit. Subgroup analyses found that clear effects were evident in women and subjects with a family history of cancer. No association with gastric cancer was observed in any subjects or subgroups. CONCLUSION: Overweight/obesity was associated with decreased risk of ESCC in this dysplasia population, particularly in women and persons who had a family history of cancer. Future studies are needed to confirm these findings.

2.
J Neuroinflammation ; 17(1): 62, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066456

RESUMO

BACKGROUND: A sustained inflammatory response following spinal cord injury (SCI) contributes to neuronal damage, inhibiting functional recovery. Macrophages, the major participants in the inflammatory response, transform into foamy macrophages after phagocytosing myelin debris, subsequently releasing inflammatory factors and amplifying the secondary injury. Here, we assessed the effect of macrophage scavenger receptor 1 (MSR1) in phagocytosis of myelin debris after SCI and explained its possible mechanism. METHODS: The SCI model was employed to determine the critical role of MSR1 in phagocytosis of myelin debris in vivo. The potential functions and mechanisms of MSR1 were explored using qPCR, western blotting, and immunofluorescence after treating macrophages and RAW264.7 with myelin debris in vitro. RESULTS: In this study, we found improved recovery from traumatic SCI in MSR1-knockout mice over that in MSR1 wild-type mice. Furthermore, MSR1 promoted the phagocytosis of myelin debris and the formation of foamy macrophage, leading to pro-inflammatory polarization in vitro and in vivo. Mechanistically, in the presence of myelin debris, MSR1-mediated NF-κB signaling pathway contributed to the release of inflammatory mediators and subsequently the apoptosis of neurons. CONCLUSIONS: Our study elucidates a previously unrecognized role of MSR1 in the pathophysiology of SCI and suggests that its inhibition may be a new treatment strategy for this traumatic condition.

3.
Cell Death Dis ; 11(2): 93, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024814

RESUMO

Osteosarcoma (OS) is a malignant bone tumor which occurs mainly in adolescents with frequent pulmonary metastasis and a high mortality rate. Accumulating evidence has indicated that microRNAs (miRNAs) play a vital role in various tumors by modulating target genes as well as signal pathways, and aberrant expression of miRNAs may contribute to OS progression. This study aimed to determine the association between miR-210-5p expression and OS progression and to investigate its potential underlying mechanism. Using reverse transcription-polymerase chain reaction (RT-PCR), miR-210-5p was found to be upregulated in clinical OS specimens and cell lines. Further functional analysis demonstrated that miR-210-5p promoted epithelial-mesenchymal transition (EMT) and induced oncogenic autophagy. Luciferase reporter assay, RNA-ChIP, and western blot analysis confirmed that PIK3R5, an essential regulator in the AKT/mTOR signaling pathway, is a target downstream gene of miR-210-5p. Overexpression or knockdown of PIK3R5 reversed the functional role of overexpression or knockdown of miR-210-5p, respectively. Silencing autophagy-related gene 5 (ATG5) abolished the functional effects of miR-210-5p upregulation or PIK3R5 knockdown in OS cells. In vivo, miR-210-5p overexpression promoted OS tumor growth and pulmonary metastasis. Taken together, our results demonstrated that miR-210-5p promoted EMT and oncogenic autophagy by suppressing the expression of PIK3R5 and regulating the AKT/mTOR signaling pathway. Therefore, inhibition of miR-210-5p may represent a promising treatment for OS.

4.
J Neuroinflammation ; 17(1): 47, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019561

RESUMO

BACKGROUND: Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction with high disability and mortality. In recent years, mesenchymal stem cell (MSC)-secreted nano-sized exosomes have shown great potential for promoting functional behavioral recovery following SCI. However, MSCs are usually exposed to normoxia in vitro, which differs greatly from the hypoxic micro-environment in vivo. Thus, the main purpose of this study was to determine whether exosomes derived from MSCs under hypoxia (HExos) exhibit greater effects on functional behavioral recovery than those under normoxia (Exos) following SCI in mice and to seek the underlying mechanism. METHODS: Electron microscope, nanoparticle tracking analysis (NTA), and western blot were applied to characterize differences between Exos and HExos group. A SCI model in vivo and a series of in vitro experiments were performed to compare the therapeutic effects between the two groups. Next, a miRNA microarray analysis was performed and a series of rescue experiments were conducted to verify the role of hypoxic exosomal miRNA in SCI. Western blot, luciferase activity, and RNA-ChIP were used to investigate the underlying mechanisms. RESULTS: Our results indicate that HExos promote functional behavioral recovery by shifting microglial polarization from M1 to M2 phenotype in vivo and in vitro. A miRNA array showed miR-216a-5p to be the most enriched in HExos and potentially involved in HExos-mediated microglial polarization. TLR4 was identified as the target downstream gene of miR-216a-5p and the miR-216a-5p/TLR4 axis was confirmed by a series of gain- and loss-of-function experiments. Finally, we found that TLR4/NF-κB/PI3K/AKT signaling cascades may be involved in the modulation of microglial polarization by hypoxic exosomal miR-216a-5p. CONCLUSION: Hypoxia preconditioning represents a promising and effective approach to optimize the therapeutic actions of MSC-derived exosomes and a combination of MSC-derived exosomes and miRNAs may present a minimally invasive method for treating SCI.

5.
FASEB J ; 34(2): 2055-2074, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31908016

RESUMO

In spinal cord ischemia-reperfusion (I/R) injury, large amounts of reactive oxygen species can cause mitochondrial damage. Therefore, mitophagy acts as the main mechanism for removing damaged mitochondria and protects nerve cells. This study aimed to illustrate the important role of GPCR kinase 2-interacting protein-1 (GIT1) in mitophagy in vivo and in vitro. The level of mitophagy in the neurons of Git1 knockout mice was significantly reduced after ischemia-reperfusion. However, the overexpression of adeno-associated virus with Git1 promoted mitophagy and inhibited the apoptosis of neurons. GIT1 regulated the phosphorylation of Beclin-1 in Thr119, which could promote the translocation of Parkin to the mitochondrial outer membrane. This process was independent of PTEN-induced kinase 1 (PINK1), but it could not rescue the role in the absence of PINK1. Overall, GIT1 enhanced mitophagy and protected neurons against ischemia-reperfusion injury and, hence, might serve as a new research site for the protection of ischemia-reperfusion injury.

6.
Neuropsychologia ; 139: 107361, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31987849

RESUMO

Cognitive control serves as a core construct, with limited capacity, to support executive functions and other higher-level mental processes such as intellectual activity. Although previous studies have investigated the development of executive functions during specific age periods, the development of the capacity of cognitive control (CCC) from early childhood to late adolescence and the heritability of the CCC have yet to be delineated. In this study, we estimated the CCC based on the performance of a perceptual decision-making task in monozygotic (n = 95) and dizygotic (n = 81) twin pairs with an age range from 6 to 18 years and in a reference young adult group (n = 41, mean age = 26.15 years). In addition, the intelligence quotient (IQ) of these participants was assessed using the Wechsler Intelligence Scales. We found an increase in the CCC from 1.55 bits per second (bps) at age 6 years to its 95% capacity of 3.87 bps at age 21 years, with a reduced growth rate as a function of age. The estimated heritability of the CCC was 0.66, and shared and non-shared environmental influences on the CCC were 0.18 and 0.16, respectively. The CCC was significantly correlated to IQ (r = 0.34). These findings indicate that the CCC is developed throughout the school years, is highly heritable, and is associated with higher-level cognition.

7.
Theranostics ; 10(1): 17-35, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31903103

RESUMO

Approximately 10% of bone fractures do not heal satisfactorily, leading to significant clinical and socioeconomic implications. Recently, the role of macrophages in regulating bone marrow stem cell (BMSC) differentiation through the osteogenic pathway during fracture healing has attracted much attention. Methods: The tibial monocortical defect model was employed to determine the critical role of macrophage scavenger receptor 1 (MSR1) during intramembranous ossification (IO) in vivo. The potential functions and mechanisms of MSR1 were explored in a co-culture system of bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and BMSCs using qPCR, Western blotting, immunofluorescence, and RNA sequencing. Results: In this study, using the tibial monocortical defect model, we observed delayed IO in MSR1 knockout (KO) mice compared to MSR1 wild-type (WT) mice. Furthermore, macrophage MSR1 mediated PI3K/AKT/GSK3ß/ß-catenin signaling increased ability to promote osteogenic differentiation of BMSCs in the co-culture system. We also identified proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) as the target gene for macrophage MSR1-activated PI3K/AKT/GSK3ß/ß-catenin pathway in the co-culture system that facilitated M2-like polarization by enhancing mitochondrial oxidative phosphorylation. Conclusion: Our findings revealed a previously unrecognized function of MSR1 in macrophages during fracture repair. Targeting MSR1 might, therefore, be a new therapeutic strategy for fracture repair.

8.
Cancer Imaging ; 20(1): 3, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907050

RESUMO

BACKGROUND: Accurate and early diagnosis of residual tumors or intrahepatic recurrences after TACE is critically needed for determining the success of treatments and for guiding subsequent therapeutic planning. This meta-analysis was performed to assess the efficacy of diffusion weighted imaging (DWI) with the quantitative apparent diffusion coefficient (ADC) value in diagnosing residual or recurrent hepatocellular carcinoma after transarterial chemoembolization (TACE). MATERIALS AND METHODS: A comprehensive literature search of PubMed, Embase, Web of Science, Scopus and the Cochrane Library database, from inception to July 2019, was conducted to select original studies on diagnosing residual or recurrent HCCs after TACE using DWI sequence with its ADC value. Two researchers independently chose study, extracted data, conducted meta-analysis, and evaluated methodological quality according to Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. RESULTS: Twelve studies comprising 624 patients and 712 tumors were finally included. The pooled sensitivity, specificity and AUC value of DWI in diagnosing residual or recurrent HCCs after TACE were 85% (95%CI: 74-92%), 83% (95%CI: 75-88%) and 0.90 (95%CI: 0.87-0.92), respectively. Residual or recurrent HCCs have significantly lower ADC value than necrotic tumors (MD = -0.48, 95%CI: - 0.69~ - 0.27, P < 0.01). CONCLUSION: This study demonstrated that DWI performed better in diagnosing residual or recurrent HCCs after TACE, and ADC value may serve as alternatives for further evaluation of residual or recurrent leisions in HCC patients after TACE.

9.
Biomater Sci ; 8(2): 702-711, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31777864

RESUMO

Although chemotherapy is the most common method in clinical therapeutics with a straightforward mechanism, conventional anti-tumor drugs are still almost incapable of preventing the occurrence of tumor metastasis. In this study, we developed a multi-functional drug delivery system EINP@DOX consisting of a tea-derived polyphenol EGCG, iron ions and DOX. The system integrated the functions of tumor inhibition, diagnosis and metastasis prevention to achieve a systematic tumor treatment. The nanoscale size of EINP@DOX facilitated its accumulation in tumor tissues by means of the enhanced permeability and retention (EPR) effect, and it was then transferred to endosomes. The weakly acidic microenvironment in the endosomes of the tumor cells could destroy the coordination structure of EINP@DOX to realize the release of DOX for tumor therapy. Furthermore, the dissociative EGCG played the role of an adjuvant to restrain EMT and down-regulate the MMP levels, which could prevent the occurrence of tumor metastasis. Meanwhile, iron ions as superior magnetic resonance imaging (MRI) contrast agents provided visual evidence for the accurate location of EINP@DOX. In vitro and in vivo studies demonstrated that EINP@DOX showed a remarkable performance in tumor diagnosis and excellent therapeutic efficacy, inhibiting the metastasis of tumor cells effectively at the same time.

10.
Cortex ; 122: 263-276, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30661735

RESUMO

Over forty years have passed since the first evidence showing the unbalanced attentional allocation of humans across the two visual fields, and since then, a wealth of behavioral, neurophysiological, and clinical data increasingly showed a right hemisphere dominance for orienting of attention. However, inconsistent evidence exists regarding the right-hemisphere dominance for executive control of attention, possibly due to a lack of consideration of its dynamics with the alerting and orienting functions. In this study, we used a version of the Attentional Network Test with lateralized presentation of the stimuli to the left visual field (processed by the right hemisphere, RH) and right visual field (processed by the left hemisphere, LH) to examine visual field differences in executive control of attention under alerting and orienting of attention. Analyses of behavioral performance (reaction time and error rate) showed a more efficient executive control (reduced conflict effect) in the RH compared to the LH for the reaction time, under conditions of increased alerting and of informative spatial orienting. These results demonstrate the right-hemisphere superiority for executive control, and that this effect depends on the involvement of the alerting and orienting functions.

11.
Anal Chim Acta ; 1093: 131-141, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31735206

RESUMO

Simple and accurate detection of trace heavy metals in blood is very important. A novel dual-responsive electrochemical/fluorescent biosensor based on magnetic hyperbranched polyamide with heparin modification (MHPAM-H) for blood lead detection has been successfully developed. Upon conjugated with blood lead ions, dual-biosensor could not only display electrochemical signal but also fluorescence signal owing to the enriched amino groups, cavity structure, and good fluorescence properties of HPAM. Blood biocompatibility, construction of the dual-responsive biosensor, electrochemical/fluorescent detection of lead ions in water phase and blood condition, selectivity and stability of the dual-responsive biosensor were investigated in detail. The proposed dual-responsive biosensor displays good linear relationship (1.5 pM- 4.8 × 103 pM for electrochemical detection and 0.5 pM-4.8 × 103 pM for fluorescent detection) with low detection limit (4.4 pM for electrochemical detection and 1.0 pM for fluorescent detection) for blood lead, providing potential application for blood lead detection in the future.

12.
Acta Biomater ; 103: 196-212, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31857259

RESUMO

Increasing evidence has suggested that paracrine mechanisms might be involved in the underlying mechanism of mesenchymal stem cells (MSCs) transplantation, and exosomes are an important component of this paracrine role. However, MSCs are usually exposed to normoxia (21% O2) in vitro but experience large differences in oxygen concentration in the body under hypoxia. Indeed, hypoxic precondition of MSCs can enhance their paracrine effects. The main purpose of this study was to determine whether exosomes derived from MSCs under hypoxia (Hypo-Exos) exhibit greater effects on bone fracture healing than those under normoxia (Exos). Using in vivo bone fracture model and in vitro experiments including cell proliferation assay, cell migration assay and so on, we confirmed that Hypo-Exos administration promoted angiogenesis, proliferation and migration to a greater extent when compared to Exos. Furthermore, utilizing a series in vitro and in vivo gain and loss of function experiments, we confirmed a functional role for exosomal miR-126 in the process of bone fracture healing. Meanwhile, we found that knockdown of hypoxia inducible factor 1 (HIF-1α) resulted in a significant decrease of miR-126 in MSCs and exosomes, thereby abolishing the effects of Hypo-Exos. In conclusion, our results demonstrated a mechanism by which Hypo-Exos promote bone fracture healing through exosomal miR-126. Moreover, hypoxia preconditioning mediated enhanced production of exosomal miR-126 through the activation of HIF-1α. Hypoxia preconditioning represents an effective and promising method for the optimization of the therapeutic actions of MSC-derived exosomes for bone fracture healing. STATEMENT OF SIGNIFICANCE: Studies have confirmed that transplantation of exosomes exhibit similar therapeutic effects and functional properties to directly-transplanted stem cells but have less significant adverse effects. However, during in vitro culture conditions, MSCs are usually exposed to normoxia (21% O2) which is very different to the oxygen concentrations found in the body under natural physiological conditions. Our results demonstrated a mechanism by which Hypo-Exos promote bone fracture healing through exosomal miR-126 and the SPRED1/Ras/Erk signaling pathway. Moreover, hypoxia preconditioning mediated enhanced production of exosomal miR-126 through the activation of HIF-1α. Hypoxia preconditioning represents an effective and promising method for the optimization of the therapeutic actions of MSC-derived exosomes for bone fracture healing.

13.
J Exp Clin Cancer Res ; 38(1): 488, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829261

RESUMO

BACKGROUND: Accumulating evidence indicates that aberrant microRNA (miRNA) expression contributes to osteosarcoma progression. This study aimed to elucidate the association between miR-624-5p expression and osteosarcoma (OS) development and to investigate its underlying mechanism. METHODS: We analyzed GSE65071 from the GEO database and found miR-624-5p was the most upregulated miRNA. The expression of miR-624-5p and its specific target gene were determined in human OS specimens and cell lines by RT-PCR and western blot. The effects of miR-624-5p depletion or ectopic expression on OS proliferation, migration and invasion were evaluated in vitro using CCK-8 proliferation assay, colony formation assay, transwell assay, would-healing assay and 3D spheroid BME cell invasion assay respectively. We investigated in vivo effects of miR-624-5p using a mouse tumorigenicity model. Besides, luciferase reporter assays were employed to identify interactions between miR-624-5p and its specific target gene. RESULTS: miR-624-5p expression was upregulated in OS cells and tissues, and overexpressing miR-624-5p led to a higher malignant level of OS, including cell proliferation, migration and invasion in vitro and in vivo. Protein tyrosine phosphatase receptor type B (PTPRB) was negatively correlated with miR-624-5p expression in OS tissues. Using the luciferase reporter assay and Western blotting, PTPRB was confirmed as a downstream target of miR-624-5p. PTPRB restored the effects of miR-624-5p on OS migration and invasion. The Hippo signaling pathway was identified as being involved in the miR-624-5p/PTPRB axis. CONCLUSIONS: In conclusion, our results suggest that miR-624-5p is a negative regulator of PTPRB and a risk factor for tumor metastasis in OS progression.

14.
Ying Yong Sheng Tai Xue Bao ; 30(11): 3716-3724, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31833684

RESUMO

Soil samples from four vegetation mini-patches (Artemisia scoparia, Glycyrrhiza uralensis, Sophora alopecuroides, Astragalus melilotoides) in a desert steppe in central Ningxia were collected. Soil physico-chemical properties including soil particle-size distribution, organic matter, pH, EC, total N, total K, total P of three depths were measured. The fractal dimension of particle size distribution characteristics of soils derived from four different vegetation mini-patches and their correlations with soil physico-chemical properties were examined. The results showed that patch vege-tation distribution affected the distribution of soil particle size, with the A. melilotoides mini-patch being the highest (D=2.51) and G. uralensis mini-patch being the lowest (D=2.46). There were significant positive correlation between fractal dimensions and the contents of clay and silt, and nega-tive correlation between fractal dimensions and sand content. Fractal dimensions were positively correlated with pH value and EC, negatively correlated with the contents of soil organic matter and total N, and had no correlation with the contents of soil total K and total P. The patchy vegetation distribution had potential trends of salinization and degradation.


Assuntos
Fractais , Solo , China , Argila , Nutrientes , Tamanho da Partícula
15.
Strahlenther Onkol ; 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748837

RESUMO

PURPOSE: The efficacy and tolerability of adding chemotherapy to radiotherapy in the era of intensity-modulated radiation therapy (IMRT) remain controversial among older patients with nasopharyngeal carcinoma (NPC). The present study compared IMRT alone with IMRT in combination with chemotherapy in elderly NPC patients. METHODS: Between January 2011 and December 2014, 102 patients aged >65 years with NPC who received IMRT alone (IMRT group) or IMRT in combination with chemotherapy (IMRT/CT group) were enrolled. Patients from both treatment arms were pair-matched (1:1 ratio) based on six clinical factors. Differences in overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier method and Cox proportional hazards models, whereas the toxicity profile was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4. RESULTS: No significant differences were noted in OS (72.1% vs. 72.5%, p = 0.799), DFS (65.9% vs. 70.1%, p = 0.733), LRRFS (76.4% vs. 71.6%, p = 0.184), and DMFS (90.8% vs. 98.0%, p = 0.610) between the IMRT and IMRT/CT groups. Multivariate analyses showed that chemotherapy was not an independent factor for OS, DFS, LRRFS, and DMFS. However, the incidences of grade 3 vomiting/nausea (p = 0.000), leukopenia/neutropenia (p = 0.000), thrombocytopenia (p = 0.041), and anemia (p = 0.040) were significantly higher in the IMRT/CT group compared with the IMRT group. No grade 4 toxicities were observed. CONCLUSION: IMRT alone was similar to IMRT/CT in treating elderly NPC patients (age >65 years), with comparable survival outcomes and less grade 3 toxicities.

16.
PLoS One ; 14(11): e0224773, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31751366

RESUMO

OBJECTIVE: To compare the efficacy of tenofovir and entecavir in nucleos(t)ide analogue-naive chronic hepatitis B. METHODS: The Web of Science, PubMed, Cochrane Library, EMBASE, Clinical Trials and China National Knowledge Infrastructure(CNKI) databases were electronically searched to collect randomized controlled trials (RCTs) regarding the comparison between tenofovir and entecavir in nucleos(t)ide analogue-naive chronic hepatitis B (CHB) since the date of database inception to July 2019. Two researchers independently screened and evaluated the obtained studies and extracted the outcome indexes. RevMan 5.3 software was used for the meta-analysis. RESULTS: Early on, tenofovir had a greater ability to inhibit the hepatitis B virus, I2 = 0% [RR = 1.08, 95% CI (1.03, 1.13), P<0.01] (96 weeks). Entecavir can normalize the ALT levels earlier, I2 = 0% [RR = 0.87, 95% CI (0.77, 0.98), P = 0.02] (48 weeks). However, there was no statistically significant difference between TDF and ETV at 144 weeks. Tenofovir was as effective as entecavir in terms of HBeAg clearance and HBeAg seroconversion, I2 = 0% [RR = 1.05, 95% CI (0.68, 1.62), P = 0.82]; I2 = 69% [RR = 0.93, 95% CI (0.54, 1.61), P = 0.80]. The difference in the incidence of elevated creatine kinase levels was not statistically significant I2 = 0% [RR = 0.66, 95% CI (0.27, 1.60), P = 0.35]. CONCLUSIONS: Tenofovir and entecavir were equally effective in the treatment of patients with nucleos(t)ide analogue-naive chronic hepatitis B. In addition, TDF has an advantage in the incidence of hepatocellular carcinoma. Additional RCTs and a large-sample prospective cohort study should be performed.

17.
J Comp Neurol ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31674015

RESUMO

Cognitive control is the coordination of mental operations under conditions of uncertainty in accordance with goal-directed behaviors, and plays a key role in the domains of executive control, working memory, and decision-making. Although there is emerging evidence of common involvement of the cognitive control network (CCN) of the brain in these domains, this network has mostly been linked to the processing of conflict, which is just one case of an increase in uncertainty. Here, we conducted an activation-likelihood-estimation-based large-scale meta-analysis of 289 functional magnetic resonance imaging studies in the three domains to examine the common involvement of the CCN in uncertainty processing by contrasting the high-uncertainty versus low-uncertainty conditions. We found a general association between increase in uncertainty and an activation increase in regions of the CCN, including the frontoparietal network (comprising the frontal eye fields, the areas near and along the intraparietal sulcus, and the dorsolateral prefrontal cortex), the cingulo-opercular network (including the anterior cingulate cortex extending to the supplementary motor area, and the anterior insular cortex), and a subcortical structure (the striatum). These results demonstrate that the CCN is a domain-general construct underlying uncertainty processing to support goal-directed behaviors.

18.
Nano Lett ; 19(11): 8049-8058, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31558023

RESUMO

Pyroptosis is a lytic and inflammatory form of programmed cell death and could be induced by chemotherapy drugs via caspase-3 mediation. However, the key protein gasdermin E (GSDME, translated by the DFNA5 gene) during the caspase-3-mediated pyroptosis process is absent in most tumor cells because of the hypermethylation of DFNA5 (deafness autosomal dominant 5) gene. Here, we develop a strategy of combining decitabine (DAC) with chemotherapy nanodrugs to trigger pyroptosis of tumor cells by epigenetics, further enhancing the immunological effect of chemotherapy. DAC is pre-performed with specific tumor-bearing mice for demethylation of the DFNA5 gene in tumor cells. Subsequently, a commonly used tumor-targeting nanoliposome loaded with cisplatin (LipoDDP) is used to administrate drugs for activating the caspase-3 pathway in tumor cells and trigger pyroptosis. Experiments demonstrate that the reversal of GSDME silencing in tumor cells is achieved and facilitates the occurrence of pyroptosis. According to the anti-tumor activities, anti-metastasis results, and inhibition of recurrence, this pyroptosis-based chemotherapy strategy enhances immunological effects of chemotherapy and also provides an important insight into tumor immunotherapy.

19.
Cell Cycle ; 18(21): 3010-3029, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31530090

RESUMO

Spinal cord injury (SCI) is a catastrophic disease which has complicated pathogenesis including inflammation, oxidative stress and glial scar formation. Astrocytes are the most abundant cells in central nervous system and fulfill homeostatic functions. Recent studies have described a new reactive phenotype of astrocytes, A1, induced by inflammation, which may have negative effects in SCI. As the Notch signaling pathway has been linked to cell differentiation and inflammation, we aimed to investigate its potential role in the differentiation of astrocytes in SCI. Contusive SCI rat model showed elevated A1 astrocyte numbers at the damage site 28 days after SCI and the expression levels of Notch signaling and its downstream genes were upregulated parallelly. Western blotting, RT-qPCR and immunofluorescence revealed that blocking of Notch pathway using γ-secretase blocker (DAPT) suppressed the differentiation of A1 astrocytes. Flow cytometry, and TUNEL staining indicated that DAPT alleviated neuronal apoptosis and axonal damage caused by A1 astrocytes likely through the Notch-dependent release of pro-inflammatory factors. CO-IP and western blotting revealed an interaction between Notch pathway and signal transducer and activator of transcription 3 (Stat3), which played a vital role in differentiation of A1 astrocytes. We conclude that phenotypic transition of A1 astrocytes and their neurotoxity were controlled by the Notch-Stat3 axis and that Notch pathway in astrocytes may serve as a promising therapeutic target for SCI.

20.
Aging (Albany NY) ; 11(18): 7723-7745, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31563124

RESUMO

Neural stem cell-derived small extracellular vesicles (NSC-sEVs) play an important role in the repair of tissue damage. Our previous in vitro and in vivo studies found that preconditioning with NSC-sEVs promoted the recovery of functional behaviors following spinal cord injury by activating autophagy. However, the underlying mechanisms for such observations remain unclear. In this study, we further explored the mechanisms by which NSC-sEVs repair spinal cord injury via autophagy. We found that NSC-sEVs contain 14-3-3t protein, of which the overexpression or knockdown enhanced and decreased autophagy, respectively. In addition, 14-3-3t overexpression enhanced the anti-apoptotic and anti-inflammatory effects of NSC-sEVs, further promoting functional behavior recovery following spinal cord injury. The overexpression of 14-3-3t was used to further validate the in vivo results through a series of in vitro experiments. Conversely, knockdown of 14-3-3t attenuated the anti-apoptotic and anti-inflammatory effects of NSC-sEVs. Further studies also confirmed that NSC-sEVs increased Beclin-1 expression, with which 14-3-3t interacted and promoted its localization to autophagosome precursors. In this study, we found that NSC-sEVs deliver 14-3-3t, which interacts with Beclin-1 to activate autophagy. Our results indicate that 14-3-3t acts via a newly-discovered mechanism for the activation of autophagy by NSC-sEVs.

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