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目的:研究大鼠肿瘤坏死因子α(TNF-α)基因5'上游序列中核因子-κB的5个结合位点(-898,-641,-610,-498,-208)在血管紧张素Ⅱ(AngⅡ)诱导乳鼠心肌细胞TNF-α表达中的作用.方法:运用脱氧核糖核酸(DNA)重组技术构建5个分别包含SD大鼠TNF-α基因5'上游不同序列(-1167~ 63 bp,-730~ 63 bp,-632~ 63 bp,-548~ 63 bp,-421~ 63 bp)的荧光素酶报告基因质粒1~5(V1~V5),转染乳鼠心肌细胞V1~V5共5组及空载体组,检测在AngⅡ刺激及核因子-κB抑制剂咖啡酸苯乙酯(CAPE)作用下心肌细胞荧光素酶比活性的变化.结果:基础状态下转染质粒V3、V4的心肌细胞荧光素酶比活性高于V5,而V5又高于V1、V2.10-8mol/L AngⅡ刺激24 h后,与对照相比,转染V5的心肌细胞荧光素酶比活性显著增加,转染V4的心肌细胞荧光素酶比活性明显下降,且V5高于V4.在AngⅡ刺激同时加入CAPE可使转染任一重组质粒的心肌细胞荧光素酶比活性显著下降,且低于对照.结论:TNF-α基因5'上游核因子-κB的5个结合位点在基础状态下,κB4(-498)、κB5(-208)位点促进TNF-α转录,κB2(-641)抑制TNF-α转录.AngⅡ通过κB3(-610)、κB5位点促进TNF-α转录,而通过κB4则抑制TNF-α转录. 相似文献
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Daniel J. Apicco Evgeny Shlevkov Catherine L. Nezich David T. Tran Edward Guilmette Justin W. Nicholatos Collin M. Bantle Yi Chen Kelly E. Glajch Neeta A. Abraham Lan T. Dang G. Campbell Kaynor Ellen A. Tsai Khanh-Dung H. Nguyen Joost Groot YuTing Liu Andreas Weihofen Jessica A. Hurt Heiko Runz Warren D. Hirst 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(1)
Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) is a ubiquitously expressed lipid kinase that inactivates IP3, a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). Genome-wide association studies have identified common variants in the ITPKB gene locus associated with reduced risk of sporadic Parkinson’s disease (PD). Here, we investigate whether ITPKB activity or expression level impacts PD phenotypes in cellular and animal models. In primary neurons, knockdown or pharmacological inhibition of ITPKB increased levels of phosphorylated, insoluble α-synuclein pathology following treatment with α-synuclein preformed fibrils (PFFs). Conversely, ITPKB overexpression reduced PFF-induced α-synuclein aggregation. We also demonstrate that ITPKB inhibition or knockdown increases intracellular calcium levels in neurons, leading to an accumulation of calcium in mitochondria that increases respiration and inhibits the initiation of autophagy, suggesting that ITPKB regulates α-synuclein pathology by inhibiting ER-to-mitochondria calcium transport. Furthermore, the effects of ITPKB on mitochondrial calcium and respiration were prevented by pretreatment with pharmacological inhibitors of the mitochondrial calcium uniporter complex, which was also sufficient to reduce α-synuclein pathology in PFF-treated neurons. Taken together, these results identify ITPKB as a negative regulator of α-synuclein aggregation and highlight modulation of ER-to-mitochondria calcium flux as a therapeutic strategy for the treatment of sporadic PD.Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by a variety of motor symptoms (including unbalanced gait, resting tremor, and bradykinesia) that are accompanied by psychosis and dementia at later stages of disease. The onset of motor symptoms is largely caused by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the corresponding depletion of dopamine innervation in the striatum. Although the cause of neuron loss is unknown, the hallmark pathological feature of PD is the presence of intraneuronal inclusions composed of misfolded and fibrillar α-synuclein (α-syn) in the neurites and soma, termed Lewy neurites and Lewy bodies, respectively (1). Protein-coding single-nucleotide polymorphisms (SNPs), duplications, and triplications in the gene encoding α-syn (SNCA) all cause early-onset, familial forms of PD and result in accelerated aggregation of α-syn protein into insoluble, fibrillar aggregates (1, 2). Recent evidence suggests that these aggregates can spread from cell to cell, leading to the propagation of pathology to neuroanatomically connected brain regions (3, 4). Therefore, therapeutic approaches that reduce the aggregation or spreading of pathological α-syn species represent potential disease-modifying therapies for PD.In addition to SNCA, mutations in several other genes have been identified that cause rare, familial forms of PD. These genes are primarily involved in the autophagic clearance of intracellular aggregates or damaged organelles, especially mitochondria (5–8). Genome-wide association studies (GWAS) have also identified common SNPs in several genes related to endolysosomal function, such as GBA and LRRK2, that are associated with increased risk of PD (8–11). GBA and LRRK2 mutations have been shown to affect lysosomal and mitochondrial phenotypes (12–14), which contribute to the accumulation of PD-like neuropathology in mouse models, primary neurons, and human iPSC-derived cells (15–18). These findings highlight the role of the lysosomal and mitochondria quality control pathways in PD and demonstrate that perturbations in these pathways are sufficient to increase α-syn aggregation. Despite this, the etiology of sporadic PD is not fully understood, and the specific genes and pathways that are tractable for therapeutic modulation remain elusive. Therefore, the discovery of new genes associated with sporadic PD may be critical for both understanding disease pathogenesis and identifying novel therapeutic approaches.Recently, Chang et al. conducted a GWAS analysis that identified 17 novel gene loci significantly associated with sporadic PD in a European population including more than 26,000 patients across three independent cohorts (19). The lead GWAS SNP in the novel 1q42 locus was rs4653767. This is an intronic SNP in the gene encoding inositol-1,4,5-triphosphate kinase B (ITPKB) and produces a thymine-to-cytosine nucleotide substitution that is protective against developing PD (odds ratio [OR] = 0.92, P = 2.4 × 10−10). A follow up meta-analysis study of 37,688 PD patients, which included the discovery cohort, and 18,618 proxy cases strengthened the GWAS finding at this locus (OR = 0.92, P = 1.4 × 10−15). Furthermore, this locus was still significant when the analysis was performed on only the new independent cases and proxy cases (OR = 0.92, P = 2.8 × 10−5) (20). The rs4653767-C allele is present in similar frequencies across populations (27% in non-Finnish European and 29% in East Asian populations) and was found to have the same direction of effect (OR = 0.87, P = 0.016) in a targeted replication study of the European PD loci in an East Asian cohort (21). ITPKB is also highly expressed in several brain regions related to PD, including the SNpc, striatum, and cerebral cortex (22).ITPKB is one of three ubiquitously expressed kinases known to phosphorylate inositol-1,4,5-triphosphate (IP3), an intracellular messenger produced from phosphatidylinositol-4,5-bisphosphate by phospholipase C (23, 24). IP3 binds to IP3 receptors (IP3Rs) in the endoplasmic reticulum (ER) to stimulate the release of calcium ions from the ER into the cytosol to mediate various downstream signaling pathways. IP3 kinases (ITPKA, ITPKB, and ITPKC) add a fourth phosphate group to IP3 producing inositol-1,3,4,5-tetrakisphosphate (IP4), which has no activity on IP3Rs. Thus, IP3 kinases negatively regulate IP3-mediated calcium release from the ER. While the role of this pathway in peripheral cell types under normal physiological conditions is well understood (25, 26), whether ITPKB is involved in the pathogenesis of PD is unknown. Here, we investigate whether the modulation of ITPKB expression or kinase activity impacts the accumulation of α-syn pathology in cellular models of PD. 相似文献
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Linchuan Wang Yan Yu Wei Chen Jin Feng Jinyuan Wang Heping Zhao Lietin Ma Bo Yang Yanfen Ma Pei Dang 《Clinical and Vaccine Immunology : CVI》2015,22(5):510-515
The purpose of this study was to evaluate the characteristics of the T-SPOT.TB test for the diagnosis of active tuberculosis (ATB) and to distinguish ATB from other diseases using a receiver operating characteristic (ROC) curve. A total of 535 patients with suspected active tuberculosis were enrolled in the study and divided into ATB and nonactive tuberculosis (NATB) groups, as well as pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) subgroups. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of the T-SPOT.TB test for the diagnosis of ATB were 84.95%, 85.12%, 82.94%, 86.93%, 5.71, and 0.18, respectively. The median number of spot-forming cells (SFCs) in the ATB group was higher than that in the NATB group (71 versus 1; P < 0.0001). The sensitivities in the PTB and EPTB subgroups were 92.31% and 81.77%. The areas under the curve (AUC) for the diagnosis of ATB using the T-SPOT.TB, early secreted antigenic target 6 (ESAT-6), and culture filtrate protein 10 (CFP-10) were 0.906, 0.884, and 0.877, respectively. A cutoff of 42.5 SFCs for ATB yielded a positive predictive value of 100%. Our study shows that the T-SPOT.TB test is useful for the diagnosis of ATB. Utilizing an ROC curve to select an appropriate cutoff made it possible to discriminate ATB from NATB. 相似文献
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Shenaz Ramtoola Edward Jude Anthony Robinson Iqbal Malik Gerrard Rayman Cuong Dang Graham David Ross Martin Amar Ali 《Journal of diabetes science and technology》2014,8(4):776-782
Background:Accurate calculation and adjustment of insulin doses is integral to maintaining glycemic control in insulin treated patients. Difficulties with insulin dose calculations may lead to poor adherence to blood glucose monitoring and insulin treatment regimes, resulting in poor metabolic control. The main objective of this study was to evaluate ease of use and user preference of a high specification touch screen blood glucose meter, which has an in-built insulin calculator, compared to patients’ usual method of testing blood glucose and deciding insulin doses.Methods:Patients with diabetes on a multiple daily injection insulin regime used the Test Meter without the insulin calculator and 1 of 3 comparator meters, each for a 7-day period. They then used the Test Meter with the in-built calculator for 10 days. Patients completed an ease of use questionnaire after each 7-day period, a preference questionnaire after the second 7-day period, and a questionnaire comparing the Test Meter with their usual method after the final 10-day period.Results:Of 164 patients who completed the study, 76% stated a preference for the Test Meter as a diabetes management tool compared to their usual method. A small number of patients preferred familiar methods and/or calculating insulin doses themselves. The log book function of meters was important to most patients.Conclusions:The Test Meter system with in-built insulin calculator supports people to better manage their diabetes and increases their confidence. Patients have different needs and preferences which should be acknowledged and supported in a patient centered health service. 相似文献
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