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1.
摘要:目的 研究丹酚酸A对Aβ42聚集的干预作用。方法 利用ThT荧光实验法探究金属Zn2+对Aβ42聚集的影响,丹酚酸A对Aβ42聚集和解聚的影响,以及对金属Zn2+诱导Aβ42聚集的干预作用;在无水乙醇溶剂中,合成丹酚酸A-Zn(Ⅱ)配合物并对其结构进行表征,从而探究丹酚酸A对金属Zn2+诱导Aβ42聚集干预作用的机制及过程。结果 金属Zn2+促进Aβ42的聚集,丹酚酸A对Aβ42的聚集具有抑制作用,对Aβ42聚集体具有解聚作用,并且能明显抑制金属Zn2+诱导Aβ42的聚集;成功在体外合成丹酚酸A-Zn(Ⅱ)配合物,根据结构表征结果,推测其可能的结构式为1分子丹酚酸A与1分子金属Zn2+通过丹酚酸A的羧基和羧基邻位的苯环形成配合物,丹酚酸A能和Aβ42竞争性的络合金属Zn2+,从而抑制金属Zn2+诱导Aβ42的聚集和促进金属Zn2+诱导Aβ42聚集体的解聚。结论 丹酚酸A具有双靶点同时抑制作用,为探索丹参治疗AD的作用机制奠定基础。  相似文献   
2.
目的探究miR-146a对胰腺腺泡细胞AR42J增殖及凋亡的影响。方法通过雨蛙素诱导AR42J细胞构建急性胰腺炎模型,酶联免疫吸附实验(ELISA)检测细胞上清液中淀粉酶、TNF-α、IL-6含量验证模型构建,qRT-PCR与Western blot分别检测各组中miR-146a和TRAF6表达量的改变。转染敲低AR42J细胞中miR-146a表达量,采用Edu检测细胞敲低后增殖改变,流式细胞术检测凋亡能力改变。结果与未处理组相比,雨蛙素组细胞miR-146a表达量显著降低(P<0.05),TRAF6表达量明显升高(P<0.05),并且敲低miR-146a后AR42J细胞增殖能力明显降低,凋亡能力明显升高。结论miR-146a可能通过抑制TRAF6表达从而降低AR42J细胞凋亡并促进细胞增殖能力。  相似文献   
3.
Background: Intraductal carcinoma and cribriform (IDC/C) tumor features are well-established prognosticators of biochemical recurrence (BCR), metastasis, and prostate cancer (PCa)-specific mortality. However, approximately 70% of PCa patients undergoing a radical prostatectomy are IDC/C negative, yet up-to 20% of these patients progress and experience BCR. Thus, tumor histopathologic characteristics such as IDC/C alone are limited in their ability to predict disease progression. Conversely, several nomograms such as Cancer of the Prostate Risk Assessment-Surgery (CAPRA-S) have been developed to aid in the prognostication of BCR, but not yet widely applied in clinical settings. Materials and methods: In this study, we assessed the combined prognostic utility of IDC/C, and CAPRA-S for BCR in 3 PCa patient cohorts. Results: CAPRA-S+IDC/C improved the predictive accuracy of BCR in all 3 cohorts (P < .001). Specifically, among IDC/C negative cases, CAPRA-S improved the prognostication of BCR in low-risk (Cohort 1; P < .001, Cohort 2; P < .001, Cohort 3; P = .003), intermediate (Cohort 1; P < .001, Cohort 2; P = .006, Cohort 3; P = .03) and high-risk (Cohort 1-3; P < .001) patients. Conversely, IDC/C improved the prognostication of BCR among CAPRA-S low-risk (Cohorts 1; P < .001 and Cohort 3; P = .003) patients. Conclusion: Our results suggest the investigation of histopathological IDC/C features in CAPRA-S low-risk patients and conversely, nomogram CAPRA-S among IDC/C negative patients improves the identification of patients likely to experience BCR, which would otherwise be missed through current assessment regimens. These patients can be offered more intensive monitoring and adjuvant therapies upfront to circumvent the development of recurrent cancer or overtreatment at the time of surgery.  相似文献   
4.
PurposeTo determine the prognostic effect of upper tract urothelial carcinoma (UTUC) with variant histology (VH) after radical nephroureterectomy (RNU).Patients and MethodsThe data of 1173 patients who received RNU for UTUC without neoadjuvant chemotherapy in 11 institutions between 2002 and 2016 were retrospectively reviewed. A matched propensity score analysis was performed. Clinicopathologic variables, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were compared between patients with pure UTUC and patients with UTUC and VH. Univariate and multivariate Cox proportional regression models were used to determine the independent variables associated with oncologic outcomes.ResultsUTUC with VH was observed in 93 patients (7.9%). After propensity score matching, UTUC with VH showed no difference in clinicopathologic features compared to pure UTUC; however, it was associated with shorter RFS, CSS, and OS (log rank, P = .011, P = .002, P = .006, respectively). Additionally, the multivariate analysis revealed that VH was independently associated with a poor RFS [hazard ratio (HR) = 1.92; 95% confidence interval (CI), 1.27-2.89; P = .002], CSS (HR = 4.47; 95% CI, 1.99-10.1; P = .001), and OS (HR = 3.00; 95% CI, 1.55-5.78; P = .001). However, the Kaplan-Meier method revealed that differences in RFS, CSS, and OS were not significant in patients who received adjuvant chemotherapy (log rank, P = .562, P = .060, P = .153, respectively).ConclusionUTUC with VH was independently associated with poor oncologic outcomes in patients with UTUC after RNU. Although patients with UTUC and VH had a poor prognosis compared to patients with pure UTUC, adjuvant chemotherapy would be helpful in improving the survival rates of these patients.  相似文献   
5.
Introduction: Alzheimer’s disease looms as a profound and growing threat to future human health. The disease is thought to be primarily driven by aberrant proteolysis of the amyloid precursor protein (APP) and amyloid beta (Aβ) plaque deposition.

Areas covered: We provide an overview of the molecular pathology that leads to an increase in Aβ peptide accumulation, of the mechanism of action for antibody mediated therapies and of the therapeutic vaccines that target Aβ under development. We also discuss the rationale for using vaccines in the early stages of the disease.

Expert opinion: The major components of β-amyloid plaques are Aβ1-42 and Aβ1-40 peptides derived from the APP. Reducing these plaques by means of passive or active vaccination against Aβ-peptides has been a long-running endeavor but with disappointing results as the impact on disease progression has been minimal. The data gathered to date could suggest that antibodies do not work, mainly because the studies have not been performed in an optimal fashion. The emerging views are that patients should be treated earlier, ideally in the prodromal or symptom free stage, antibody levels have to be high and the correct epitope must be targeted. More clinical trials to fully explore the potential of vaccines are therefore warranted.  相似文献   

6.
BACKGROUND Acute pancreatitis(AP) is a sudden inflammatory process of the pancreas that may also involve surrounding tissues and/or remote organs. Inflammation and parenchymal cell death are common pathological features of this condition and determinants of disease severity. Polyethylene glycols(PEGs) are nonimmunogenic, non-toxic water-soluble polymers widely used in biological, chemical, clinical and pharmaceutical settings.AIM To evaluate the protective effect of a 35-k Da molecular weight PEG(PEG35) on the pancreatic damage associated to cerulein-induced acute pancreatitis in vivo and in vitro.METHODS Wistar rats were assigned at random to a control group, a cerulein–induced AP group and a PEG35 treatment group. AP was induced by five hourly intraperitoneal injections of cerulein(50 μg/kg/bw), while the control animals received saline solution. PEG35 was administered intraperitoneally 10 minutes before each cerulein injection in a dose of 10 mg/kg. After AP induction, samples of pancreatic tissue and blood were collected for analysis. AR42 J pancreatic acinar cells were treated with increasing concentrations of PEG35 prior to exposure with tumor necrosis factor α(TNFα), staurosporine or cerulein. The severity of AP wasdetermined on the basis of plasma levels of lipase, lactate dehydrogenase activity, pancreatic edema and histological changes. To evaluate the extent of the inflammatory response, the gene expression of inflammation-associated markers was determined in the pancreas and in AR42 J-treated cells. Inflammation-induced cell death was also measured in models of in vivo and in vitro pancreatic damage.RESULTS Administration of PEG35 significantly improved pancreatic damage through reduction on lipase levels and tissue edema in cerulein-induced AP rats. The increased associated inflammatory response caused by cerulein administration was attenuated by a decrease in the gene expression of inflammation-related cytokines and inducible nitric oxide synthase enzyme in the pancreas. In contrast, pancreatic tissue m RNA expression of interleukin 10 was markedly increased. PEG35 treatment also protected against inflammation-induced cell death by attenuating lactate dehydrogenase activity and modulating the pancreatic levels of apoptosis regulator protein BCL-2 in cerulein hyperstimulated rats. Furthermore, the activation of pro-inflammatory markers and inflammationinduced cell death in pancreatic acinar cells treated with TNFα, cerulein or staurosporine was significantly reduced by PEG35 treatment, in a dose-dependent manner.CONCLUSION PEG35 ameliorates pancreatic damage in cerulein-induced AP and AR42 J-treated cells through the attenuation of the inflammatory response and associated cell death. PEG35 may be a valuable option in the management of AP.  相似文献   
7.
Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naïve T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function.Dendritic cells (DCs) are crucial for the initiation of an adaptive immune response. Upon acquiring antigens in the periphery, DCs undergo a maturation process that includes antigen processing, cytokine production, and up-regulation of costimulatory molecules. A mature DC must then migrate from peripheral tissues to draining lymph nodes (LNs) to fulfill its role as an antigen-presenting cell that primes naïve T cells (1). Although the signals that induce this maturation process are now well-established (1), relatively little is understood about DC migration aside from the primary chemotactic cue provided by CCR7 that guides DCs to the LN (2, 3).We recently described a genetically modified NLRP10 (NLR family, pyrin domain containing 10) knockout strain in which this migration step was disrupted while leaving the remainder of the DC maturation program, including CCR7 expression, intact (4). NLRP10 is the only NOD-like receptor (NLR) without a leucine-rich repeat domain, the putative pathogen-associated molecular pattern (PAMP)–binding domain. It has been proposed to both positively and negatively regulate other NLRs, such as NOD1 and NLRP3, respectively (5, 6). Although we found that NLRP3 inflammasome activation was unaltered in the absence of NLRP10, we discovered that Nlrp10−/− mice could not mount a productive T- or B-cell immune response due to a DC-intrinsic failure to emigrate out of inflamed tissues (4, 7).To understand the mechanism by which NLRP10 governs DC migration, we used an expression proteomic approach to identify molecules with altered expression in DCs generated from the Nlrp10−/− strain and discovered a profound reduction in DOCK8 (dedicator of cytokinesis 8). DOCK8 is a guanine nucleotide exchange factor (GEF) that has two functional domains, DOCK homology region (DHR) 1 and DHR2 (8). In murine DCs, the DHR2 domain has been implicated in regulating the Rho GTPase CDC42 (cell division control protein 42 homolog), which in turn maintains cell polarity of mature DCs during migration (9, 10). Furthermore, mice harboring inactivating mutations in Dock8 lack marginal zone B-cell development, long-term antibody production following immunization, and memory CD8+ T-cell responses to viral infections (11, 12). In humans, inactivating mutations in Dock8 were recently identified as the primary genetic cause underlying autosomal recessive hyper-IgE syndrome (13). This syndrome presents with eczema, recurrent infections of the skin and respiratory tract, increased serum IgE, eosinophilia, recurrent fungal and viral infections, extensive food and environmental allergies, and, in certain patients, squamous cell dysplasia and carcinomas (14).Given that DOCK8 regulates a wide array of immunologic processes in mouse and human, we sought to understand how NLRP10 regulates DOCK8. To our surprise, we discovered that loss of DOCK8 in the Nlrp10−/− strain was secondary to a point mutation within the Dock8 gene itself. In this study, we demonstrate that restoring DOCK8 function in the Nlrp10−/− strain leads to normal DC migration in vivo. We further show that deletion of Dock8, as well as spontaneous mutation of Dock8 in another inbred strain of mice, results in defective DC migration and, depending on the degree of impaired migration, also abrogates CD4+ T-cell activation.  相似文献   
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