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1.
Br J Pharmacol ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32232832

RESUMO

BACKGROUND AND PURPOSE: To investigate the vasorelaxant effect of glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 on retinal capillaries under normal and ischemia-reperfusion (I/R) conditions. EXPERIMENTAL APPROACH: The regulation of capillary diameters by exendin-4 on whole-mounted retina was directly observed using the infrared differential interference contrast microscopy. A rat model of retinal I/R was established using high perfusion pressure in an anterior chamber. To observe the possible protective role of exendin-4, the peptide drug was administered through subcutaneous injection, intravitreal injection, or eye drops. The underlying mechanism was explored by immunofluorescence, qPCR, and Simple Western. KEY RESULTS: Immunofluorescence staining showed that GLP-1R was expressed in the endothelial cells of retinal capillaries. Exendin-4 significantly relaxed the capillaries pre-contracted by noradrenaline, which was abolished by denuding endothelium with CHAPS and inhibited by GLP-1R antagonist exendin-9-39, endothelium nitric oxide synthase (eNOS) inhibitor L-NAME, and the guanylate cyclase blocker ODQ, but not by cyclooxygenase inhibitor indomethacin. Retina capillary was constricted in I/R injury and perfusion of exendin-4 could restored it effectively. The expression level of PI3K and AKT, phosphorylation level of eNOS, and NO production in I/R group was lower than that in the normal control group, and the administration of exendin-4 improved the changes. CONCLUSION AND IMPLICATION: Exendin-4 can restore injured microvascular patency in I/R. Exendin-4 may regulate retinal capillaries through the GLP-1R-PI3K/AKT-eNOS/NO-cGMP pathway. Therefore, exendin-4 may be an effective treatment for improving tissue perfusion in I/R-related diseases.

2.
Zhongguo Zhong Yao Za Zhi ; 45(1): 142-148, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237423

RESUMO

The aim of this paper was to observe the effect of Realgar and arsenic trioxide on gut microbiota. The mice were divided into low-dose Realgar group(RL), medium-dose Realgar group(RM), high-dose Realgar group(RH), and arsenic trioxide group(ATO), in which ATO and RL groups had the same trivalent arsenic content. Realgar and arsenic trioxide toxicity models were established after intragastric administration for 1 week, and mice feces were collected 1 h after intragastric administration on day 8. The effects of Realgar on gut microbiota of mice were observed through bacterial 16 S rRNA gene sequences. The results showed that Lactobacillus was decreased in all groups, while Ruminococcus and Adlercreutzia were increased. The RL group and ATO group were consistent in the genera of Prevotella, Ruminococcus, and Adlercreutzia but different in the genera of Lactobacillus and Bacteroides. Therefore, the effects of Realgar and arsenic trioxide with the same amount of trivalent arsenic on gut microbiota were similar, but differences were still present. Protective bacteria such as Lactobacillus were reduced after Realgar administration, causing inflammation. At low doses, the number of anti-inflammatory bacteria, such as Ruminococcus, Adlercreutzia and Parabacteroides increased, which can offset the slight inflammation caused by the imbalance of bacterial flora. At high doses, the flora was disturbed and the number of Proteobacteria was increased, with aggravated intestinal inflammation, causing edema and other inflammatory reactions. Based on this, authors believe that the gastrointestinal reactions after clinical use of Realgar may be related to flora disorder. Realgar should be used at a small dose in combination with other drugs to reduce intestinal inflammation.

3.
Biomed Res Int ; 2020: 4150735, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190664

RESUMO

Objective: The aim of this study was to investigate the expression of Snail, galectin-3, and IGF1R in benign and malignant pheochromocytoma and paraganglioma (PPGL) and explore their role in the diagnosis of malignant PPGL. Methods: We retrospectively collected and analyzed surgical tumor tissue from 226 patients initially diagnosed with PPGL who underwent surgery from Jan. 2009 to Jan. 2016 at West China Hospital, Sichuan University. We observed and quantified the expression of Snail, galectin-3, and IGF1R in paraffin-embedded samples by immunohistochemical staining. Results: The significant difference in survival time among the three groups (benign PHEO, benign PGL, and potentially malignant PPGL) was compared by Kaplan-Meier survival analysis. The positive staining of Snail, galectin-3, and IGF1R in the benign PHEO group was significantly lower than that in the other three groups (P < 0.001). The Kaplan-Meier survival plots indicated that the survival time of the patients with intense positive staining was significantly lower than that of the patients with weak positive staining. Conclusion: The intense expression of Snail, galectin-3, and IGF1R may be valuable indicators for the diagnosis of malignant PPGL.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32193337

RESUMO

Methionine metabolism is critical for the maintenance of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) pluripotency. However, little is known about the regulation of the methionine cycle to sustain ESC pluripotency. Here, we show that adenosylhomocysteinase (AHCY), an important enzyme in the methionine cycle, is critical for the maintenance and differentiation of mouse embryonic stem cells (mESCs). We show that mESCs exhibit high levels of methionine metabolism, whereas decreasing methionine metabolism via depletion of AHCY promotes mESCs to differentiate into the three germ layers. AHCY is posttranslationally modified with an O-linked ß-N-acetylglucosamine sugar (O-GlcNAcylation), which is rapidly removed upon differentiation. O-GlcNAcylation of threonine 136 on AHCY increases its activity and is important for the maintenance of trimethylation of histone H3 lysine 4 (H3K4me3) to sustain mESC pluripotency. Blocking glycosylation of AHCY decreases the ratio of S-adenosylmethionine versus S-adenosylhomocysteine (SAM/SAH), reduces the level of H3K4me3, and poises mESC for differentiation. In addition, blocking glycosylation of AHCY reduces somatic cell reprogramming. Thus, our findings reveal a critical role of AHCY and a mechanistic understanding of O-glycosylation in regulating ESC pluripotency and differentiation.

5.
Asian J Androl ; 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32167077

RESUMO

Membrane-associated guanylate kinase (MAGUK) family protein MAGUK invert 2 (MAGI-2) has been demonstrated to be involved in the tumorigenic mechanism of prostate cancer. The objective of this study was to investigate the expression of MAGI-2 at mRNA and protein levels. The prognostic value of MAGI-2 in Han Chinese patients with prostate cancer was also investigated. The expression data of MAGI-2 were assessed through database retrieval, analysis of sequencing data from our group, and tissue immunohistochemistry using digital scoring system (H-score). The clinical, pathological, and follow-up data were collected. The expression of MAGI-2 in prostate tumor tissues and prostate normal tissues was evaluated and compared. MAGI-2 expression was associated with clinical parameters including tumor stage, lymph node status, Gleason score, PSA level, and biochemical recurrence of prostate cancer. The relative expression of MAGI-2 mRNA was lower in the tumor tissue in The Cancer Genome Atlas (TCGA) database and sequencing data (P < 0.001). There was no difference in MAGI-2 protein expression between tumor and normal tissues in tissue microarray (TMA) results. MAGI-2 expression was associated with pathological tumor stage (P = 0.02), Gleason score (P = 0.05), and preoperation prostate-specific antigen (PSA; P = 0.04). A positive correlation was identified between MAGI-2 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expressions through the analysis of TCGA and TMA data (P < 0.0001). Patients with higher MAGI-2 expression had longer biochemical recurrence-free survival in the univariate analysis (P = 0.005), which indicates an optimal prognostic value of MAGI-2 in Han Chinese patients with prostate cancer. In conclusion, MAGI-2 expression gradually decreases with tumor progression, and can be used as a predictor of tumor recurrence in Chinese patients.

6.
Am J Trop Med Hyg ; 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32207401

RESUMO

Strongyloidiasis affects an estimated hundreds of millions of people worldwide, with infection possibly persisting for life without appropriate therapy because of the helminth's unique autoinfection cycle. Like other soil-transmitted helminths, because of the environmental conditions required for the life cycle of Strongyloides stercoralis, this parasite is endemic to tropical, subtropical, and temperate countries and areas with inadequate sanitation infrastructure. Given continued poverty and that nearly one in five American homes are lacking proper sanitation systems, many U.S. regions are at risk for intestinal parasites. A central Texas community was chosen as the study site, given previous reports of widespread sanitation failure, degree of poverty, and community willingness to participate. A total of 92 households were surveyed and residents tested for nine intestinal parasites using a multi-parallel quantitative real-time PCR and ELISA serology. From 43 stool samples, 27 (62.8%) tested positive for Blastocystis spp. and one (2.3%) for Giardia lamblia. From 97 serum samples, Strongyloides serology detected 16 (16.5%) positive individuals. These high rates of heterokont and helminthic laboratory findings in a peri-urban central Texas community suggest several key policy implications, including that strongyloidiasis should be added to the Texas notifiable conditions list, that clinical suspicion for this infection should be heightened in the region, and that residents without access to functioning and sustainable sanitation infrastructure should be provided that access as a basic human right and to promote public health.

7.
Sci Total Environ ; 722: 137892, 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32199385

RESUMO

Establishing an optimal indicator to communicate health risks of multiple air pollutants to public is much important. The Air Quality Health Index (AQHI) has been developed in many countries as a communication tool of multiple air pollutants related health risks. However, the current AQHI is based on the sum of the excess health risks which are typically derived from the single-pollutant statistical models. Such a strategy may overestimate the joint effect of multiple pollutants. We proposed an improved strategy to construct the AQHI based on a Bayesian multipollutant weighted model. Using this strategy, two improved indices - Bayesian multipollutant AQHI (BMP-AQHI) and Bayesian multipollutant AQHI with seasonal specificity (SBMP-AQHI) were calculated to present the multiple pollutants related health risks to the cardiovascular system based on data collected in Chengdu, China during 2013 to 2018. The two improved indices were compared to current Air Quality Index (AQI) and AQHI to evaluate the effectiveness of the improved indices in characterizing multipollutant health risks. The AQI risk classification suggested much smaller health risks than AQHIs. Among three AQHI types, the BMP-AQHI and SBMP-AQHI suggested slightly lower health risks to the cardiovascular system than the current AQHI. In the evaluation analysis, the SBMP-AQHI had the strongest association with the mortality of cardiovascular disease (CVD) (2.66%; 95%CI, 1.57%, 3.76%). In the subgroup analysis, an interquartile increase (IQR) of the SBMP-AQHI was associated with 3.21% (95%CI, 2.06%, 4.38%), 1.34% (95%CI, -0.13%, 2.82%), and 4.20% (95%CI, 2.59%, 5.84%) increases for CVD mortality in the elderly, male, and female subgroups, respectively. The study shows that the improved AQHIs can communicate the health information of multiple air pollutants more efficiently. The study also indicates the necessity to consider seasonal specificity in the construction of the AQHI.

8.
Front Immunol ; 11: 18, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32082311

RESUMO

CD47 is an immunoglobulin that is overexpressed on the surface of many types of cancer cells. CD47 forms a signaling complex with signal-regulatory protein α (SIRPα), enabling the escape of these cancer cells from macrophage-mediated phagocytosis. In recent years, CD47 has been shown to be highly expressed by various types of solid tumors and to be associated with poor patient prognosis in various types of cancer. A growing number of studies have since demonstrated that inhibiting the CD47-SIRPα signaling pathway promotes the adaptive immune response and enhances the phagocytosis of tumor cells by macrophages. Improved understanding in this field of research could lead to the development of novel and effective anti-tumor treatments that act through the inhibition of CD47 signaling in cancer cells. In this review, we describe the structure and function of CD47, provide an overview of studies that have aimed to inhibit CD47-dependent avoidance of macrophage-mediated phagocytosis by tumor cells, and assess the potential and challenges for targeting the CD47-SIRPα signaling pathway in anti-cancer therapy.

9.
Biomaterials ; 235: 119769, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31986348

RESUMO

Tumor associated fibroblasts (TAFs) are key stromal cells mediating the desmoplastic reaction and being partially responsible for the drug-resistance and immunosuppressive microenvironment formation in solid tumors. Delivery of genotoxic drugs off-targetedly to kill TAFs results in production of Wnt16 which renders the neighboring tumor cells drug resistant as shown in our previous study (PMC4623876). Our current approach looks for means to deactivate, rather than kill, TAFs. Reactive oxygen species (ROS) are the central hub of multiple profibrogenic pathways and indispensable for TAFs activation. Herein, puerarin was identified to effectively downregulate ROS production in the activated myofibroblast. In this study, a novel puerarin nanoemulsion (nanoPue) was developed to improve the solubility and bioavailability of puerarin. NanoPue significantly deactivated the stromal microenvironment (e.g., ~6-fold reduction of TAFs in nanoPue treated mice compared with the PBS control, p < 0.0001) and facilitated chemotherapy effect of nano-paclitaxel in the desmoplastic triple-negative breast cancer (TNBC) model. Moreover, the removal of the physical barrier increased intra-tumoral infiltration of cytotoxic T cell by 2-fold. This activated immune microenvironment allowed nanoPue to synergize PD-L1 blockade therapy in TNBC model.

10.
Endocr Pract ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31968187

RESUMO

Aims: To characterize the relationship between diabetic retinopathy (DR) and diabetic nephropathy (DN) in Chinese patients and to determine whether the severity of DR predicts end-stage renal disease (ESRD). Methods: Bilateral fundic photographs of 91 Chinese type 2 diabetic patients with biopsy-confirmed DN, not in ESRD stage, were obtained at the time of renal biopsy in this longitudinal study. The baseline severity of DR was determined using the Lesion-aware Deep Learning System (RetinalNET) in an open framework for deep learning and was graded using the Early Treatment Diabetic Retinopathy Study Severity Scale. Cox proportional hazard models were used to estimate the hazard ratio (HR) for the effect of the severity of diabetic retinopathy on ESRD. Results: During a median follow-up of 15 months, 25 patients progressed to ESRD. The severity of retinopathy at the time of biopsy was a prognostic factor for progression to ESRD (HR 2.18, 95% confidence interval (CI) 1.05-4.53, P= 0.04). At baseline, more severe retinopathy was associated with poor renal function, and more severe glomerular lesions. However, 30% patients with mild retinopathy and severe glomerular lesions had higher low-density lipoprotein-cholesterol and more severe proteinuria than those with mild glomerular lesions. Additionally, 3% of patients with severe retinopathy and mild glomerular changes were more likely to have had diabetes a long time than those with severe glomerular lesions. Conclusions: Although the severity of DR predicted diabetic ESRD in patients with T2DM and DN, the severities of DR and DN were not always consistent, especially in patients with mild retinopathy or microalbuminuria.

11.
Drug Dev Ind Pharm ; 46(2): 283-295, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31944130

RESUMO

In this study, we evaluated and screened the effects of the molecular weight (MW) and molar ratio of poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate (PEtOz-CHMC) on the pH sensitivity, stability, and antitumor efficacy of liposomes. The pH sensitivity of PEtOz-CHMC with different MWs and molar ratios was screened by drug release and cytotoxicity experiments at different pH levels. Results indicated that the liposomes coated with PEtOz1k-CHMC (7% molar ratio) and PEtOz2k-CHMC (5% molar ratio) exhibited the desirable pH responsiveness. When the MW of PEtOz was relatively low, 7% of the modified ratio obtained the strongest stability, but the turbidity of the liposomes did not obviously change when the molar ratio of PEtOz-CHMC was further increased. A375 cells were used as models to investigate the cellular uptake and intracellular localization of coumarin-6-loaded liposomes (C6-L), PEGylated liposomes (PEG-C6-L), and PEtOzylated liposomes. PEtOz1k-C6-L and PEtOz2k-C6-L presented remarkably stronger fluorescence intensity at low pH than at pH 7.4, whereas C6-L and PEG-C6-L did not achieve any obvious diversity at different pH conditions. Compared with C6-L and PEG-C6-L, PEtOz-C6-L showed efficient intracellular trafficking, including endosomal/lysosomal escape and cytoplasmic release. Pharmacokinetic experiments demonstrated that half-lives of PEG2k-C6-L, PEtOz2k-C6-L, and PEtOz1k-C6-L were 11.89-, 7.00-, and 5.29-fold times higher than those of C6-L, respectively. Among the liposomes, the DOX·HCl-loaded liposomes coated with PEtOz2k-CHMC demonstrated the strongest antitumor efficacy against B16 tumor xenograft models in vivo. These findings provide the feasibility of using PEtOz-CHMC with optimal pH sensitivity and long circulation to extend the application of liposomes to efficient anticancer drug delivery.

12.
Neuron ; 105(2): 293-309.e5, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31901304

RESUMO

The molecular mechanisms that govern the maturation of oligodendrocyte lineage cells remain unclear. Emerging studies have shown that N6-methyladenosine (m6A), the most common internal RNA modification of mammalian mRNA, plays a critical role in various developmental processes. Here, we demonstrate that oligodendrocyte lineage progression is accompanied by dynamic changes in m6A modification on numerous transcripts. In vivo conditional inactivation of an essential m6A writer component, METTL14, results in decreased oligodendrocyte numbers and CNS hypomyelination, although oligodendrocyte precursor cell (OPC) numbers are normal. In vitro Mettl14 ablation disrupts postmitotic oligodendrocyte maturation and has distinct effects on OPC and oligodendrocyte transcriptomes. Moreover, the loss of Mettl14 in oligodendrocyte lineage cells causes aberrant splicing of myriad RNA transcripts, including those that encode the essential paranodal component neurofascin 155 (NF155). Together, our findings indicate that dynamic RNA methylation plays an important regulatory role in oligodendrocyte development and CNS myelination.


Assuntos
Adenosina/análogos & derivados , Diferenciação Celular/fisiologia , Metiltransferases/fisiologia , Bainha de Mielina/fisiologia , Oligodendroglia/citologia , Oligodendroglia/fisiologia , RNA Mensageiro/metabolismo , Adenosina/metabolismo , Animais , Moléculas de Adesão Celular/metabolismo , Contagem de Células , Linhagem da Célula , Células Cultivadas , Feminino , Masculino , Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Camundongos Transgênicos , Fatores de Crescimento Neural/metabolismo , Células Precursoras de Oligodendrócitos/fisiologia
13.
Endocr Pract ; 26(1): 51-57, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31557073

RESUMO

Objective: Our study sought to investigate the clinicopathologic features and renal prognosis of patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) in different age groups. Methods: A total of 315 patients with T2DM and biopsy-proven DN were enrolled and divided into three groups by age: the Youth group (≤44 years old), the Middle-aged group (45 to 59 years old), and the Elderly group (≥60 years old). Results: The Youth group, Middle-aged group, and Elderly group accounted for 19.05% (60/315), 59.37% (187/315), and 21.59% (68/315) of the patients in our study, respectively. The patients in the Youth group had a higher estimated glomerular filtration rate (calculated using the Chronic Kidney Disease-Epidemiology collaboration formula) (P<.001), a higher incidence of diabetic retinopathy (P = .044), and a higher incidence of being in the lower-risk chronic kidney disease heat map category (P = .046) but lower duration of diabetes (P = .016). Histologically, patients in the Youth group had the highest incidence of glomerular classification in class I (P = .006) and arteriolar hyalinosis score of 0 (P = .005). The renal survival among the three groups was comparable (P>.05). Conclusion: This study indicated that there were different clinicopathologic features among Chinese DN patients in different age groups. Although the Youth group had a relatively lower rapid kidney disease progression rate, there were no significant differences in renal survival rate among the three groups, which calls more attention to early supervision and prevention for younger DN patients. Abbreviations: CKD = chronic kidney disease; DN = diabetic nephropathy; DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; G&Y&O = green and yellow and orange; IFTA = interstitial fibrosis and tubular atrophy; T2DM = type 2 diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Adulto , Idoso , Taxa de Filtração Glomerular , Humanos , Rim , Pessoa de Meia-Idade , Prognóstico
14.
Environ Pollut ; 257: 113548, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31733961

RESUMO

Existing studies have typically investigated only the association between single pollutants and health outcomes. However, in the real world, people are exposed to multiple air pollutants simultaneously. The effect of air pollutants on emergency department (ED) visits has not been previously studied in the Sichuan Basin, which is one of the most polluted areas. We collected nonaccidental, respiratory and cardiovascular daily ED visits and daily concentrations of PM2.5, PMc, CO, SO2, NO2 and O3 in Chengdu, China, from 2014 to 2016. A weighted variable for the combination of multiple air pollutants was constructed to assess the joint adverse health effects. Each air pollutant was assigned a health-related weight, which indicated the pollutant's relative contribution to the joint effect. The effects on specific subpopulations (males and females; 15-65 years old and >65 years old) were also examined. With an increase of 10 µg/m3 of the combined multiple air pollutants, the daily ED visits for nonaccidental, respiratory and cardiovascular causes increased by 0.96% (95% CI: 0.51%-1.39%), 1.19% (95% CI: 0.53%, 1.85%) and 4.36% (95% CI: 1.06%, 7.76%) at lag 1, respectively. Males presented more pronounced effects, except for cardiovascular disease, than females. Elderly individuals were found to be more sensitive than young individuals. For nonaccidental and respiratory diseases, the contributions of particulate matter (PM) were dominant among the air pollutants, whereas cardiovascular disease was mainly affected by gaseous air pollutants. The combination of multiple air pollutants was significantly associated with ED visits in the Sichuan Basin, China. The joint effect of the combination of multiple air pollutants was highest for cardiovascular disease at lag 1. The relative contributions of individual pollutants varied by disease and subpopulation. These findings suggest that under different pollution scenarios, preventive strategies should target those with different diseases and different subpopulations.

15.
Biochem Biophys Res Commun ; 522(3): 684-689, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31785807

RESUMO

Aberrant activation of Notch1 signaling frequently occurs in T-cell acute lymphoblastic leukemia (T-ALL). Notch1 activation causes release of intracellular Notch1 (ICN1, the activated form of Notch1) from cell membrane to cytoplasm. As a transcription factor, ICN1 must be transferred into nucleus and bind to the promoters of its downstream target genes. E3 ubiquitin ligase induces ICN1 degradation in cytoplasm, which blocks ICN1 transfer into the nucleus. Flavone is a natural plant polyphenol, demonstrated to have anti-cancer effects in vitro and in vivo in breast and colon cancers. However, the effects of flavone on leukemia have not been reported. In this study, we demonstrated that flavone inhibited cell proliferation by down-regulating Notch1 signal pathway in CCRF-CEM and Molt-4 T-ALL cells. Flavone-mediated upregulation of c-Cbl level results in the increase in its interaction with ICN1, further caused ICN1 ubiquitinylation and degradation. Knockdown of c-Cbl reversed flavone-induced down-regulation of ICN1 and inhibition of cell proliferation in T-ALL cells. In short, this study indicated that flavone exerted resistance to T-ALL by promoting c-Cbl-induced ubiquitinylation and degradation of ICN1.

16.
Biochem Biophys Res Commun ; 522(1): 26-32, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31735338

RESUMO

Early secreted antigenic target 6-kDa protein (ESAT6) is an essential virulence factor of Mycobacterium tuberculosis (MTb). However, ESAT6 helped fighting MTb infection according to vaccine studies. It's unclear whether ESAT6 confers protection via enhancing the innate immunity of macrophages, which are the first-line defense against MTb. We profiled the global transcriptional changes and characterized the innate immunity of THP-1 macrophages treated with ESAT6. We found ESAT6 promoted the phagocytosis ability, enhanced reactive oxygen species (ROS) generation and accelerated glucose metabolism in macrophages. Meanwhile, ESAT6 induced a distinctive phenotype of macrophages with a concurrence of pro-inflammatory and anti-inflammatory cytokines and chemokines. ESAT6 increased the expression of HIF1α mRNA and protein. Interfering HIF1α with siRNA defected the capacity of phagocytosis and ROS generation as well as glucose metabolism. Thus, ESAT6 enhanced the protective innate immunity of macrophages partially via HIF1α. This study provided clues for developing therapies against tuberculosis by targeting ESAT6.

17.
Cancer Control ; 26(1): 1073274819887697, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31793344

RESUMO

To evaluate the diagnostic value of α-methylacyl-CoA racemase (AMACR) score in Han Chinese patients with prostate cancer (PCa) through urine sediment analysis. We collected 292 urine sediment samples after digital rectal examination. Levels of AMACR and prostate-specific antigen (PSA) messenger RNA (mRNAs) were evaluated by quantitative real time-polymerase chain reaction. The diagnostic value of AMACR score was assessed by receiver-operating characteristic analysis (ROC), Mann-Whitney test, logistic regression analysis and decision curve analysis. In all patients (n = 292), the area under the curve (AUC) for serum PSA, AMACR score, and a combinative model of these 2 parameters were 0.745 (95% confidence interval [CI]: 0.691-0.794), 0.753 (95% CI: 0.700-0.802), and 0.784 (95% CI: 0.732-0.830). No statistical difference was found between AMACR score and serum PSA (P = .826), while the combinative model was better than AMACR score (Z = 5.222, P < .001). Among patients with serum PSA level of 4 to 10 ng/mL (n = 121), the AMACR score was significantly higher in patients with PCa (P = 0.0002), while serum PSA showed no difference (P = 0.3023). Alpha-methylacyl-CoA racemase score (AUC = 0.712, 95% CI: 0.623-0.790) and a combinative model (AUC = 0.714, 95% CI: 0.626-0.793) showed a better diagnostic value than serum PSA (AUC = 0.559, 95% CI: 0.466-0.649), (P = .048, P = .042). Decision curve analysis showed a biopsy prediction model including AMACR score have a better net benefit when the threshold probability greater than 20%. The diagnostic model combing serum PSA and AMACR score has a better diagnostic value in patients with abnormal PSA level (including PSA level ranging from 4-10 ng/mL), and could reduce unnecessary prostate biopsy in clinical use.

18.
Front Med ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784918

RESUMO

This study aimed to investigate the prevalence, clinical characteristics, and prognostic impact of 1p32.3 deletion in patients with newly diagnosed multiple myeloma (MM). A retrospective analysis was conducted on 411 patients with newly diagnosed MM; among which, 270 received bortezomib-based therapies, and 141 received thalidomide-based therapies. Fluorescence in situ hybridization (FISH) was performed to detect six cytogenetic abnormalities, namely, del(1p32.3), gain(1q21), del(17p13), del(13q14), t(4;14), and t(11;14). Results showed that 8.3% of patients with MM were detected with del(1p32.3) and had significantly more bone marrow plasma cells (P = 0.025), higher ß2-microglobulin levels (P = 0.036), and higher lactate dehydrogenase levels (P = 0.042) than those without del(1p32.3). Univariate analysis showed that patients with del(1p32.3) under thalidomide-based therapies (median PFS 11.6 vs. 31.2 months, P = 0.002; median OS 16.8 vs. 45.9 months, P < 0.001) were strongly associated with short progression-free survival (PFS) (P = 0.002) and overall survival (OS) (P < 0.001). Multivariate analysis revealed that del(1p32.3) remained a powerful independent factor with worse PFS (P = 0.006) and OS (P = 0.016) for patients under thalidomide-based treatments. Patients with del(1p32.3) under bortezomib-based treatments tended to have short PFS and OS. In conclusion, del(1p32.3) is associated with short PFS and OS in patients with MM who received thalidomide- or bortezomib-based treatments.

19.
Sci Rep ; 9(1): 19680, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31873148

RESUMO

Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease characterized by an autoimmune-mediated destruction of intrahepatic bile ducts. E26 transformation specific sequence 1 (ETS-1) is a transcription factor regulating the expression of various immune-related genes. The aim of our study was to identify the associations between the gene polymorphisms of ETS-1 with the susceptibility and clinical characteristics of PBC in Chinese Han population. Three single nucleotide polymorphisms (rs4937333, rs11221332 and rs73013527) of ETS-1 were selected based on relevant studies. Genotyping was executed with polymerase chain reaction-high resolution melting (PCR-HRM) assay. SNP rs4937333 of ETS-1 was prominent correlation with the susceptibility of PBC (P = 0.007, OR = 1.44, 95%CI = 1.10-1.88). For rs4937333, PBC patients carrying the allele T assumed high-level TP (P = 0.020), and homozygous genotype TT assumed low-level RDW (P = 0.033). For rs11221332, PBC patients carrying the allele T assumed high-level TP and HDLC (P = 0.004, P = 0.015, respectively). For rs73013527, PBC patients carrying the allele T assumed low-level PLT (P = 0.002), and homozygous genotype TT assumed high-level RDW (P = 0.021). In conclusion, Gene polymorphisms of ETS-1 present relevant with the susceptibility of PBC, and affect the expression of TP, HDLC, PLT and RDW concentrations in patients with PBC.

20.
Huan Jing Ke Xue ; 40(9): 4169-4176, 2019 Sep 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854882

RESUMO

To recover nitrogen and phosphorus from the supernatant of anaerobic fermentation of excess sludge in the form of struvite (MAP, MgNH4PO4·6H2O), the optimum conditions of nitrogen and phosphorus dissolution and the effects of different reaction conditions on nitrogen and phosphorus recovery were studied. The results showed that the concentration of ammonia nitrogen and orthophosphate that dissolved in the fermentation liquid peaked on the fifth day of the experiment at pH 10.5 and 35℃. When a phosphorus source was and was not added, the optimum conditions for recovering phosphorus were pH=9.5, N:P=0.8, and Mg:P=1.8 and pH=9.5, Mg:P=1.6, and speed=200 r·min-1, respectively. In addition, reducing the N:P molar ratio had a significant effect on the morphology and purity of the struvite. Scanning electron microscopy (SEM), energy dispersive spectrometry (EDS), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) were used to analyze the surface appearance and phase composition of the recovered products. The main component of the precipitate was MAP. Recovery of nitrogen and phosphorus in excess sludge in the form of struvite is an effective means for realizing sludge resource utilization.

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