• 【白细胞介素28A重组腺病毒 (Ad-mIFN-λ2) 转染的肺腺癌在体内的抑制作用。】 复制标题 收藏 收藏
    DOI:10.1089/cbr.2012.1247 复制DOI
    作者列表:Yan Y,Zhang J,Liu Y,Zhu T,Yuan L,Ge Y,Ding H,Bu X
    BACKGROUND & AIMS: :Abstract Type III interferon (IFN-λ) is a novel member of the interferon family, which preferentially promotes antiviral responses from epithelial cells and cooperates with type I IFNs in the clearance of viral infections. However, the effect of mIFN-λ2 to the LA795 lung adenocarcinoma cell is largely unknown. In this study, we transfected Ad-mIFN-λ2 vector into LA795 tumor-bearing mice to explore the effect of mIFN-λ2 on the proliferation of LA795 lung adenocarcinoma cell and on the immune response of the mice. Transfected by Ad-mIFN-λ2 vector, a significant decrease in the tumor growth, the subcutaneous tumor necrosis, cystic degeneration, and tumor apoptosis were more evident; at the same time, mIFN-λ2 protein and gene were significantly more expressed. And, flow cytometry analysis suggested that CD3(+)CD4(+), CD3(+)CD8(+), and NK (CD3(-)CD49(+)) cells were all significantly increased after transfected by Ad-mIFN-λ2. The study demonstrated that recombinant Ad-mIFN-λ2 transfection effectively inhibited the growth of LA795 lung adenocarcinoma cell, which may work through inducing apoptosis of tumor cell and regulating cell immune response.
    背景与目标: : 摘要III型干扰素 (IFN-λ) 是干扰素家族的新成员,它优先促进上皮细胞的抗病毒反应,并与I型IFN协同清除病毒感染。然而,mIFN-λ2对LA795肺腺癌细胞的作用在很大程度上是未知的。在这项研究中,我们将Ad-mIFN-λ2载体转染到LA795荷瘤小鼠中,以探讨mIFN-λ2对LA795肺腺癌细胞增殖和小鼠免疫反应的影响。转染Ad-mIFN-λ2载体后,肿瘤生长明显减少,皮下肿瘤坏死、囊性变性和肿瘤凋亡更明显; 同时,mIFN-λ2蛋白和基因表达明显更多。流式细胞术分析表明,Ad-mIFN-λ2转染后,CD3(+)CD4(+) 、CD3(+)CD8(+) 和NK (CD3(-)CD49(+) 细胞均显著增加。研究表明,重组Ad-mIFN-λ2转染可有效抑制LA795肺腺癌细胞的生长,可能通过诱导肿瘤细胞凋亡和调节细胞免疫反应而起作用。
  • 【阿尔茨海默氏病的非转基因小鼠模型 (icv-stz小鼠): 与转基因模型 (3xTg-AD小鼠) 的相似性和差异。】 复制标题 收藏 收藏
    DOI:10.1007/s12035-012-8375-5 复制DOI
    作者列表:Chen Y,Liang Z,Blanchard J,Dai CL,Sun S,Lee MH,Grundke-Iqbal I,Iqbal K,Liu F,Gong CX
    BACKGROUND & AIMS: :Alzheimer's disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and result from multiple etiologic factors, including environmental, genetic, and metabolic factors, whereas FAD is caused by mutations in the presenilins or amyloid-β (Aβ) precursor protein (APP) genes. A commonly used animal model for AD is the 3xTg-AD transgenic mouse model, which harbors mutated presenilin 1, APP, and tau genes and thus represents a model of FAD. There is an unmet need in the field to characterize animal models representing different AD mechanisms, so that potential drugs for SAD can be evaluated preclinically in these animal models. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), the icv-STZ mouse, shows many aspects of SAD. In this study, we compared the non-cognitive and cognitive behaviors as well as biochemical and immunohistochemical alterations between the icv-STZ mouse and the 3xTg-AD mouse. We found that both mouse models showed increased exploratory activity as well as impaired learning and spatial memory. Both models also demonstrated neuroinflammation, altered synaptic proteins and insulin/IGF-1 (insulin-like growth factor-1) signaling, and increased hyperphosphorylated tau in the brain. The most prominent brain abnormality in the icv-STZ mouse was neuroinflammation, and in the 3xTg-AD mouse it was elevation of hyperphosphorylated tau. These observations demonstrate the behavioral and neuropathological similarities and differences between the icv-STZ mouse and the 3xTg-AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.
    背景与目标: : 阿兹海默症 (AD) 可分为散发性AD (SAD) 和家族性AD (FAD)。大多数AD病例是散发性的,是由多种病因引起的,包括环境,遗传和代谢因素,而FAD是由presenilins或淀粉样蛋白-β (a β) 前体蛋白 (APP) 基因突变引起的。AD的常用动物模型是3xTg-AD转基因小鼠模型,该模型具有突变的早老蛋白1,APP和tau基因,因此代表了FAD模型。在本领域中,对代表不同AD机制的动物模型进行表征的需求尚未得到满足,因此可以在这些动物模型中进行临床前评估SAD的潜在药物。通过脑室内 (icv) 施用链脲佐菌素 (STZ) 生成的小鼠模型,即icv-stz小鼠,显示了SAD的许多方面。在这项研究中,我们比较了icv-stz小鼠和3xTg-AD小鼠之间的非认知和认知行为以及生化和免疫组织化学改变。我们发现,两种小鼠模型都显示出增加的探索活动以及受损的学习和空间记忆。两种模型还显示了神经炎症,突触蛋白和胰岛素/IGF-1 (胰岛素样生长因子-1) 信号的改变,以及大脑中过度磷酸化的tau增加。Icv-stz小鼠中最突出的大脑异常是神经炎症,而3xTg-AD小鼠则是过度磷酸化的tau升高。这些观察结果证明了icv-stz小鼠和3xTg-AD小鼠模型之间的行为和神经病理学异同,并将有助于指导使用这两种小鼠模型开发AD药物的未来研究。
  • 【AD-LIBS: 使用低覆盖率序列数据推断杂交基因组的祖先。】 复制标题 收藏 收藏
    DOI:10.1186/s12859-017-1613-0 复制DOI
    作者列表:Schaefer NK,Shapiro B,Green RE
    BACKGROUND & AIMS: BACKGROUND:Inferring the ancestry of each region of admixed individuals' genomes is useful in studies ranging from disease gene mapping to speciation genetics. Current methods require high-coverage genotype data and phased reference panels, and are therefore inappropriate for many data sets. We present a software application, AD-LIBS, that uses a hidden Markov model to infer ancestry across hybrid genomes without requiring variant calling or phasing. This approach is useful for non-model organisms and in cases of low-coverage data, such as ancient DNA. RESULTS:We demonstrate the utility of AD-LIBS with synthetic data. We then use AD-LIBS to infer ancestry in two published data sets: European human genomes with Neanderthal ancestry and brown bear genomes with polar bear ancestry. AD-LIBS correctly infers 87-91% of ancestry in simulations and produces ancestry maps that agree with published results and global ancestry estimates in humans. In brown bears, we find more polar bear ancestry than has been published previously, using both AD-LIBS and an existing software application for local ancestry inference, HAPMIX. We validate AD-LIBS polar bear ancestry maps by recovering a geographic signal within bears that mirrors what is seen in SNP data. Finally, we demonstrate that AD-LIBS is more effective than HAPMIX at inferring ancestry when preexisting phased reference data are unavailable and genomes are sequenced to low coverage. CONCLUSIONS:AD-LIBS is an effective tool for ancestry inference that can be used even when few individuals are available for comparison or when genomes are sequenced to low coverage. AD-LIBS is therefore likely to be useful in studies of non-model or ancient organisms that lack large amounts of genomic DNA. AD-LIBS can therefore expand the range of studies in which admixture mapping is a viable tool.
    背景与目标:
  • 【Ad GV.EGR.TNF.11D (TNFerade) 的I期剂量递增研究™生物) 在复发性头颈癌接受再照射的患者中同时进行放化疗。】 复制标题 收藏 收藏
    DOI:10.1093/annonc/mds523 复制DOI
    作者列表:Seiwert TY,Darga T,Haraf D,Blair EA,Stenson K,Cohen EE,Salama JK,Villaflor V,Witt ME,Lingen MW,Weichselbaum RR,Vokes EE
    BACKGROUND & AIMS: BACKGROUND:AdGV.EGR.TNF.11D (TNFerade™ Biologic) is a replication-deficient adenoviral vector expressing human tumor necrosis factor alpha (TNF-α) under the control of the chemoradiation-inducible EGR-1 promoter. TNF-α has been shown to function as a radiation sensitizer. We conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of TNFerade™ Biologic, when added to chemoradiotherapy in poor prognosis patients with recurrent, previously irradiated head and neck cancer (HNC). METHODS:TNFerade™ Biologic was injected intratumorally on day 1 of each 14-day cycle and dose-escalated in log increments from 4 × 10(9) to 4 × 10(11) PU. Daily radiation, infusional 5-fluorouracil (5-FU), and hydroxyurea were given on days 1-5 for seven cycles (FHX). Tumor biopsies were obtained before, during, and after treatment. RESULTS:Fourteen patients were treated. DLT was reached at a dose level of 3 (4 × 10(11) PU) with three thrombotic events. The response rate was 83.3%. The median survival was 9.6 months. One patient (7.1%) remained alive 3 years after treatment. Biopsies were obtained in 90% of patients. Nearly all tumors expressed adenovirus receptors, TNF-α, and TNF-α receptors. Adenoviral DNA was detected in three biopsies from one patient. CONCLUSIONS:TNFerade™ Biologic can be safely integrated with FHX chemoradiotherapy at an MTD of 4 × 10(10) PU. Monitoring for thrombotic events is indicated.
    背景与目标:
  • 【运动对瘦瘦和超重/肥胖男性和女性食欲,随意摄入能量和食欲调节激素的急性影响。】 复制标题 收藏 收藏
    DOI:10.1038/ijo.2017.181 复制DOI
    作者列表:Douglas JA,King JA,Clayton DJ,Jackson AP,Sargeant JA,Thackray AE,Davies MJ,Stensel DJ
    BACKGROUND & AIMS: BACKGROUND:Acute exercise does not elicit compensatory changes in appetite parameters in lean individuals; however, less is known about responses in overweight individuals. This study compared the acute effects of moderate-intensity exercise on appetite, energy intake and appetite-regulatory hormones in lean and overweight/obese individuals. METHODS:Forty-seven healthy lean (n=22, 11 females; mean (s.d.) 37.5 (15.2) years; 22.4 (1.5) kg m-2) and overweight/obese (n=25, 11 females; 45.0 (12.4) years, 29.2 (2.9) kg m-2) individuals completed two, 8 h trials (exercise and control). In the exercise trial, participants completed 60 min treadmill exercise (59 (4)% peak oxygen uptake) at 0-1 h and rested thereafter while participants rested throughout the control trial. Appetite ratings and concentrations of acylated ghrelin, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) were measured at predetermined intervals. Standardised meals were consumed at 1.5 and 4 h and an ad libitum buffet meal was provided at 7 h. RESULTS:Exercise suppressed appetite (95% confidence interval (CI) -3.1 to -0.5 mm, P=0.01), and elevated delta PYY (95% CI 10 to 17 pg ml-1, P<0.001) and GLP-1 (95% CI 7 to 10 pmol l-1, P<0.001) concentrations. Delta acylated ghrelin concentrations (95% CI -5 to 3 pg ml-1, P=0.76) and ad libitum energy intake (95% CI -391 to 346 kJ, P=0.90) were similar between trials. Subjective and hormonal appetite parameters and ad libitum energy intake were similar between lean and overweight/obese individuals (P⩾0.27). The exercise-induced elevation in delta GLP-1 was greater in overweight/obese individuals (trial-by-group interaction P=0.01), whereas lean individuals exhibited a greater exercise-induced increase in delta PYY (trial-by-group interaction P<0.001). CONCLUSIONS:Acute moderate-intensity exercise transiently suppressed appetite and increased PYY and GLP-1 in the hours after exercise without stimulating compensatory changes in appetite in lean or overweight/obese individuals. These findings underscore the ability of exercise to induce a short-term energy deficit without any compensatory effects on appetite regardless of weight status.
    背景与目标:
  • 【错误信息、错误行为、错误指导和错误陈述的荟萃分析。在重度抑郁症 (MDD) 中使用抗抑郁药 (AD)。】 复制标题 收藏 收藏
    DOI:10.1111/bdi.12893 复制DOI
    作者列表:Vinberg M
    BACKGROUND & AIMS: -2
    背景与目标: -2
  • 【为断奶后增益选择和未选择的小鼠随意喂养和限制喂养的比较。二.胴体组成和能量效率。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Timon VM,Eisen EJ,Leatherwood JM
    BACKGROUND & AIMS: -2
    背景与目标: -2
  • 【在AD细胞模型中,芹菜素通过抗氧化,线粒体保护和MAPK信号失活减轻铜介导的 β-淀粉样蛋白神经毒性。】 复制标题 收藏 收藏
    DOI:10.1016/j.brainres.2012.11.019 复制DOI
    作者列表:Zhao L,Wang JL,Wang YR,Fa XZ
    BACKGROUND & AIMS: :Apigenin, belonging to a less toxic and non-mutagenic flavone subclass of flavonoids, has been reported to possess numerous biological activities beneficial to health. Although evidence has shown apigenin might exert its protective effects by reducing the toxicity induced by amyloid-β peptides (Aβ), the precise mechanism is unclear. In the present study, we investigated the in vitro neuroprotective activity of apigenin interrelated with amyloid toxicity and mental homeostasis in an Alzheimer's disease (AD) cell model and explored its potential signal transduction. Our results showed that apigenin protected neurons against Aβ-mediated toxicity induced by copper, which was characterized by increasing neuronal viability and relieving mitochondrial membrane dissipation and neuronal nuclear condensation. Further, we demonstrated that apigenin did not provide sufficient effect on decreasing β-amyloid precursor protein (AβPP) expression and lowering Aβ(1-42) secretion, but conserved redox balance by increasing intracellular glutathione levels and enhancing cellular superoxide dismutase and glutathione peroxidase activities, reduced intracellular reactive oxygen species (ROS) generation, blocked ROS-induced p38 mitogen-activated protein kinases (p38 MAPK)- MAPKAP kinase-2 (MK2)-heat shock protein 27 (Hsp27) and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)-c-Jun signaling pathways, preserved mitochondrial function, and then regulated apoptotic pathways. In conclusion, apigenin could exert neuroprotection against Aβ-induced toxicity in the presence of copper mainly through the mechanisms that regulate redox imbalance, preserve mitochondrial function, inhibit MAPK pathways, and depress neuronal apoptosis.
    背景与目标: 芹菜素属于黄酮类中毒性较低且非致突变的黄酮类,据报道具有多种有益于健康的生物活性。尽管有证据表明芹菜素可能通过降低淀粉样 β 肽 (a β) 诱导的毒性发挥其保护作用,但确切的机制尚不清楚。在本研究中,我们在阿尔茨海默氏病 (AD) 细胞模型中研究了芹菜素与淀粉样蛋白毒性和精神稳态相关的体外神经保护活性,并探索了其潜在的信号转导。我们的结果表明,芹菜素保护神经元免受铜诱导的a β 介导的毒性,其特征是增加神经元活力,减轻线粒体膜耗散和神经元核浓缩。此外,我们证明芹菜素对降低 β-淀粉样蛋白前体蛋白 (a β pp) 表达和降低a β(1-42) 分泌没有足够的作用,但通过增加细胞内谷胱甘肽水平和增强细胞超氧化物歧化酶和谷胱甘肽过氧化物酶活性来保持氧化还原平衡,细胞内活性氧 (ROS) 生成减少,阻断ROS诱导的p38丝裂原活化蛋白激酶 (p38 MAPK)- MAPKAP激酶-2 (MK2)-热休克蛋白27 (Hsp27) 和应激活化蛋白激酶 (SAPK)/c-6月N端激酶 (JNK)-c-6月信号通路,保留线粒体功能,进而调控凋亡途径。总之,芹菜素可以通过调节氧化还原失衡,保留线粒体功能,抑制MAPK途径和抑制神经元凋亡的机制,在铜存在下对a β 诱导的毒性发挥神经保护作用。
  • 【查令十字医院儿童发展中心: 对其工作的描述,对第385名患者的评估。】 复制标题 收藏 收藏
    DOI:10.1111/j.1365-2214.1977.tb00064.x 复制DOI
    作者列表:Jolly H,Finnie NR,Hall DM,Newton RC,Roussounis SH
    BACKGROUND & AIMS: :Charing Cross Hospital provides facilities for the study of handicapped children in a normal nursery which forms part of its Child Development Centre. The period of assessment varies from one day to three weeks; the advantages of prolonged assessment are discussed. Parental involvement and support, and the teaching of medical students are emphasized. A study of the Centre's first 385 patients is presented.
    背景与目标: : 查令十字医院为在普通托儿所中研究残疾儿童提供设施,该托儿所是其儿童发展中心的一部分。评估期从一天到三周不等; 讨论了长期评估的优势。强调父母的参与和支持,以及医学生的教学。介绍了该中心第385名患者的研究。
  • 【MAPT单倍型分层gwa揭示了AD风险变异的差异关联。】 复制标题 收藏 收藏
    DOI:10.1002/alz.12099 复制DOI
    作者列表:Strickland SL,Reddy JS,Allen M,N'songo A,Burgess JD,Corda MM,Ballard T,Wang X,Carrasquillo MM,Biernacka JM,Jenkins GD,Mukherjee S,Boehme K,Crane P,Kauwe JS,Ertekin-Taner N,Alzheimer's Disease Genetics Consortium.
    BACKGROUND & AIMS: INTRODUCTION:MAPT H1 haplotype is implicated as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD). METHODS:Using Alzheimer's Disease Genetics Consortium (ADGC) genome-wide association study (GWAS) data (n = 18,841), we conducted a MAPT H1/H2 haplotype-stratified association to discover MAPT haplotype-specific AD risk loci. RESULTS:We identified 11 loci-5 in H2-non-carriers and 6 in H2-carriers-although none of the MAPT haplotype-specific associations achieved genome-wide significance. The most significant H2 non-carrier-specific association was with a NECTIN2 intronic (P = 1.33E-07) variant, and that for H2 carriers was near NKX6-1 (P = 1.99E-06). The GABRG2 locus had the strongest epistasis with MAPT H1/H2 variant rs8070723 (P = 3.91E-06). Eight of the 12 genes at these loci had transcriptome-wide significant differential expression in AD versus control temporal cortex (q < 0.05). Six genes were members of the brain transcriptional co-expression network implicated in "synaptic transmission" (P = 9.85E-59), which is also enriched for neuronal genes (P = 1.0E-164), including MAPT. DISCUSSION:This stratified GWAS identified loci that may confer AD risk in a MAPT haplotype-specific manner. This approach may preferentially enrich for neuronal genes implicated in synaptic transmission.
    背景与目标:
  • 【Ad-bFGF-siRNA和Ad-Vpr联合抗肿瘤作用对裸鼠移植瘤生长的影响。】 复制标题 收藏 收藏
    DOI:10.1007/s12253-010-9303-5 复制DOI
    作者列表:Zhang B,Feng X,Wang J,Xu X,Lin N,Liu H
    BACKGROUND & AIMS: :Basic fibroblast growth factor (bFGF) has been demonstrated to correlate with glioma grade and clinical outcome and has established its possible usefulness as a target for glioma therapy. Vpr has been described as an antitumor agent and displays a potent antitumor nature. Here, we try to investigate whether a combined treatment with bFGF-siRNA and Vpr gene would have a enhanced effectiveness on glioma in vitro and in vivo.After treatments with only Ad-bFGF-siRNA, only Ad-Vpr, and a combination of both, we assessed the changes in cell proliferation, cell cycle, and apoptosis in vitro by the methods of MTT, PI and FITC-AnnexinV double staining, respectively. In addition, we also evaluated the combined effect of bFGF-siRNA and Vpr gene therapy on glioma in vivo using xenograft glioma models in nude mice. Combined Ad-bFGF-siRNA and Ad-Vpr treatment was more better successful in inhibiting cell proliferation in comparison with treatments of either Ad-bFGF-siRNA or Ad-Vpr alone. Treatment of Ad-Vpr alone or a treatment of a combination of Ad-bFGF-siRNA and Ad-Vpr induced the G2/M cell cycle arrest and apoptosis; however, combined treatment was more effective than the Ad-Vpr treatment alone. Although each single treatment can slow the growth of xenograft glioma, the combined treatment with Ad-bFGF-siRNA and Ad-Vpr was better than either the Ad-bFGF-siRNA or Ad-Vpr treatment alone. Our results suggest that the combination therapy with bFGF-siRNA and Vpr gene can achieve a enhanced activity of anti-glioma, supporting the idea that the combination of these two antitumor agents could open new perspectives in glioma therapy.
    背景与目标: : 碱性成纤维细胞生长因子 (bFGF) 已被证明与神经胶质瘤分级和临床结果相关,并已确定其作为神经胶质瘤治疗靶标的可能用途。Vpr已被描述为抗肿瘤剂,并具有有效的抗肿瘤性质。在这里,我们试图研究用bFGF-siRNA和Vpr基因联合治疗是否能在体外和体内增强对神经胶质瘤的疗效。在仅用Ad-bFGF-siRNA,仅用Ad-Vpr和两者结合治疗后,我们评估了细胞增殖的变化,分别通过MTT,PI和FITC-AnnexinV双重染色的方法进行细胞周期和体外凋亡。此外,我们还使用裸鼠异种移植瘤神经胶质瘤模型评估了bFGF-siRNA和Vpr基因治疗对神经胶质瘤的联合作用。与单独使用Ad-bFGF-siRNA或Ad-Vpr治疗相比,Ad-bFGF-siRNA和Ad-Vpr联合治疗在抑制细胞增殖方面更成功。单独治疗Ad-Vpr或联合治疗Ad-bFGF-siRNA和Ad-Vpr可诱导G2/M细胞周期停滞和凋亡; 然而,联合治疗比单独的Ad-Vpr治疗更有效。尽管每种单一治疗都可以减缓异种移植神经胶质瘤的生长,但Ad-bFGF-siRNA和Ad-Vpr的联合治疗优于单独的Ad-bFGF-siRNA或Ad-Vpr治疗。我们的结果表明,bFGF-siRNA和Vpr基因的联合治疗可以增强抗神经胶质瘤的活性,这支持了这两种抗肿瘤药物的结合可以为神经胶质瘤治疗开辟新的前景的想法。
  • 【参之灵口服液PI3K/Akt-mTOR通路对AD小鼠髓磷脂损伤的研究。】 复制标题 收藏 收藏
    DOI:10.1177/2058738420923907 复制DOI
    作者列表:Wang Y,Chen F,Wang P,Mana L,Sheng N,Huang S
    BACKGROUND & AIMS: :Shenzhiling oral liquid (SZL) is a Traditional Chinese Medicine (TCM) compound to be approved by the China Food and Drug Administration (CFDA) (Z20120010) for the treatment of mild-to-moderate Alzheimer's disease (AD). However, its mechanism in early AD is not clear. We studied its mechanism in protecting myelin. Three-month-old APPswe/PS1dE9double transgenic mice were used as AD model and wild-type C57BL/6 mice were used as control. After 3-month intervention, the Morris water maze was used to detect behavioural changes. Myelin mTOR pathway (PI3K, p-PI3K, Akt, p-Akt, mTOR, p-mTOR), myelin basic protein (MBP) and postsynaptic density protein 95 (PSD95) were detected by immunohistochemistry and western blot and reverse transcriptase polymerase chain reaction (RT-PCR). After 3 months of SZL treatment, compared with the model group (M), SZL medium-dose (SM) and SZL low-dose groups (SL) exhibited increased staying and crossing results in Morris water maze (P < 0.05). Compared with M, PI3K-positive cells in SM and SL groups were increased (P < 0.01), p-PI3K expression increased in the Donepezil group (D), SZL high-dose group (SH) and SM (P < 0.05); number of Akt-positive cells and Akt expression in D, SM and SL were increased (P < 0.01, P < 0.05); number of p-Akt- and mTOR-positive cells and mTOR expression in all drug-treated groups were significantly increased (P < 0.01); p-Akt and p-mTOR expression increased in all drug-treated groups (P < 0.05, P < 0.01); MBP expression in D and SH increased (P < 0.05), while in SM and SL it increased more significantly (P < 0.01); and PSD95 expression in D, SM and SL was increased (P < 0.05). RT-PCR results showed that compared with M, PI3K mRNA and Akt mRNA expression in all drug-treated groups increased, but there was no statistical difference (P > 0.05), mTOR mRNA expression in all the drug-treated groups increased significantly (P < 0.01) and MBP mRNA and PSD95 mRNA expression in D and SH increased (P < 0.05). SZL oral liquid could play a role in myelin protection in early AD.
    背景与目标: : 参之灵口服液 (SZL) 是经中国食品药品监督管理局 (CFDA) (Z20120010) 批准用于治疗轻中度阿尔茨海默氏病 (AD) 的中药 (TCM) 化合物。然而,它在公元早期的机制并不清楚。我们研究了其保护髓磷脂的机制。3个月大的APPswe/ps1de9双转基因小鼠作为AD模型,野生型C57BL/6小鼠作为对照。干预3个月后,使用Morris水迷宫检测行为变化。免疫组织化学、western blot和逆转录酶聚合酶链反应 (rt-pcr) 检测髓鞘mTOR通路 (PI3K、p-PI3K、Akt、p-Akt、mTOR、p-mTOR) 、髓鞘碱性蛋白 (MBP) 和突触后密度蛋白95 (PSD95)。SZL治疗3个月后,与模型组 (M) 相比,SZL中剂量组 (SM) 和SZL低剂量组 (SL) 在Morris水迷宫中的停留和交叉结果增加 (p  <  0.05)。与M组相比,SM组和SL组PI3K-positive细胞增加 (p  <  0.01),多奈哌齐组 (D) 、SZL高剂量组 (SH) 和SM组 (p  <  0.05) p-PI3K表达增加; D组Akt阳性细胞数和Akt表达增加,SM和SL升高 (p  <  0.01,p  <  0.05); 所有药物治疗组p-Akt和mTOR阳性细胞数和mTOR表达均显着增加 (p  <  0.01); p-Akt和p-mTOR在所有药物治疗组中表达增加 (p  <  0.05,p  <  0.01); MBP在D和SH中的表达增加 (p  <  0.05),而在SM和SL中的表达增加更明显 (p  <  0.01); PSD95在D、SM和SL中的表达增加 (p  <  0.05)。Rt-pcr结果显示,与M相比,所有药物治疗组PI3K mRNA和Akt mRNA的表达均增加,但无统计学差异 (p  >  0.05)。所有药物处理组mTOR mRNA表达均显着增加 (p  <  0.01),D和SH MBP mRNA和PSD95 mRNA表达增加 (p  <  0.05)。SZL口服液可在AD早期发挥髓鞘保护作用。
  • 【早期11C-PIB框架和18F-FDG PET测量具有可比性: 一项在AD和FTLD患者队列中得到验证的研究。】 复制标题 收藏 收藏
    DOI:10.2967/jnumed.110.082057 复制DOI
    作者列表:Rostomian AH,Madison C,Rabinovici GD,Jagust WJ
    BACKGROUND & AIMS: UNLABELLED:The availability of new PET ligands offers the potential to measure fibrillar β-amyloid in the brain. Nevertheless, physiologic information in the form of perfusion or metabolism may still be useful in differentiating causes of dementia during life. In this study, we investigated whether early (11)C-Pittsburgh compound B ((11)C-PIB) PET frames (perfusion (11)C-PIB [pPIB]) could provide information equivalent to blood flow and metabolism. First, we assessed the similarity of pPIB and (18)F-FDG PET images in a test cohort with various clinical diagnoses (n = 10), and then we validated the results in a cohort of patients with Alzheimer disease (AD) (n = 42; mean age ± SD, 66.6 ± 10.6 y; mean Mini-Mental State Examination [MMSE] score ± SD, 22.2 ± 6.0) or frontotemporal lobar degeneration (FTLD) (n = 31; age ± SD, 63.9 ± 7.1 y, mean MMSE score ± SD, 23.8 ± 6.7). METHODS:To identify the (11)C-PIB frames best representing perfusion, we ran on a test cohort an iterative algorithm, including generating normalized (cerebellar reference) perfusion pPIB images across variable frame ranges and calculating Pearson R values of the sum of these pPIB frames with the sum of all (18)F-FDG frames (cerebellar normalized) for all brain tissue voxels. Once this perfusion frame range was determined on the test cohort, it was then validated on an extended cohort and the power of pPIB in differential diagnosis was compared with (18)F-FDG by performing a logistic regression of regions-of-interest tracer measure (pPIB or (18)F-FDG) versus diagnosis. RESULTS:A 7-min window, corresponding to minutes 1-8 (frames 5-15), produced the highest voxelwise correlation between (18)F-FDG and pPIB (R = 0.78 ± 0.05). This pPIB frame range was further validated on the extended AD and FTLD cohort across 12 regions of interest (R = 0.91 ± 0.09). A logistic model using pPIB was able to classify 90.5% of the AD and 83.9% of the FTLD patients correctly. Using (18)F-FDG, we correctly classified 88.1% of AD and 83.9% of FTLD patients. The temporal pole and temporal neocortex were significant discriminators (P < 0.05) in both models, whereas in the model with pPIB the frontal region was also significant. CONCLUSION:The high correlation between pPIB and (18)F-FDG measures and their comparable performance in differential diagnosis are promising in providing functional information using (11)C-PIB PET data. This approach could be useful, obviating (18)F-FDG scans when longer-lived amyloid imaging agents become available.
    背景与目标:
  • 【一项随机交叉试验,以确定在随意设置中蛋白质与碳水化合物预负荷对能量平衡的影响。】 复制标题 收藏 收藏
    DOI:10.1186/s12937-019-0497-4 复制DOI
    作者列表:Gibson MJ,Dawson JA,Wijayatunga NN,Ironuma B,Chatindiara I,Ovalle F,Allison DB,Dhurandhar EJ
    BACKGROUND & AIMS: BACKGROUND:Although high protein diets have been tested in controlled environments for applications to weight management, it is not understood if adding high protein foods to the diet would impact ad libitum energy balance in the absence of other lifestyle changes. METHODS:This double-blinded randomized crossover trial compared the effects of a protein shake (PS) to a carbohydrate shake (CS), consumed prior to each major meal to equate to 20% of total energy needs over the course of the day, on energy balance over two 5-day treatment periods in healthy adults with BMI 20-30 kg/m2. Tri-axial accelerometers estimated physical activity energy expenditure. Ad libitum energy intake was measured in a laboratory kitchen. RESULTS:Energy balance was positive during both treatment periods but was not different between periods. There were no interactions between treatment and preload caloric dose or treatment and BMI status on energy balance. Satiety ratings did not differ for any pairwise comparisons between treatment and caloric dose. Controlling for gender and basal metabolic rate, thermic effect of food was greater for PS than CS. CONCLUSIONS:Preload periods significantly altered the macronutrient composition of the overall diet. This study found limited evidence that carbohydrate or protein preloads have differential effects on energy balance in short-term ad libitum settings. TRIAL REGISTRATION:This trial was pre-registered on clinicaltrials.gov as NCT02613065 on 11/30/2015.
    背景与目标:
  • 【阿尔茨海默病 (AD) 的前驱肠道事件: 结肠动力障碍和炎症与肠道AD相关蛋白沉积有关。】 复制标题 收藏 收藏
    DOI:10.3390/ijms21103523 复制DOI
    作者列表:
    BACKGROUND & AIMS: :Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer's disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. SAMP8 mice underwent Morris water maze and assessment of faecal output at four, six and eight months of age. In vitro colonic motility was examined. Faecal and colonic Aβ, tau proteins, α-synuclein and IL-1β were assessed by ELISA. Colonic citrate synthase activity was assessed by spectrophotometry. Colonic NLRP3, caspase-1 and ASC expression were evaluated by Western blotting. Colonic eosinophil density and claudin-1 expression were evaluated by immunohistochemistry. The effect of Aβ on NLRP3 signalling and mitochondrial function was tested in cultured cells. Cognitive impairment and decreased faecal output occurred in SAMP8 mice from six months. When compared with SAMR1, SAMP8 animals displayed: (1) impaired in vitro colonic contractions; (2) increased enteric AD-related proteins, IL-1β, active-caspase-1 expression and eosinophil density; and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, Aβ promoted IL-1β release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC-/- cells. Aβ decreased mitochondrial function in THP-1 cells. In SAMP8, enteric AD-related proteins deposition, inflammation and impaired colonic excitatory neurotransmission, occurring before the full brain pathology development, could contribute to bowel dysmotility and represent prodromal events in AD.
    背景与目标: 越来越多的证据表明,肠道功能障碍可能代表阿尔茨海默病的早期事件,并导致大脑病理。这项研究在脑病理全面发展之前,研究了自发性AD模型中认知障碍的发作与结肠功能障碍之间的关系。SAMP8小鼠在四个,六个月和八个月大时接受了Morris水迷宫并评估了粪便输出量。检查了体外结肠运动。通过ELISA评估粪便和结肠a β,tau蛋白,α-突触核蛋白和IL-1β。通过分光光度法评估结肠柠檬酸合酶活性。通过蛋白质印迹法评估结肠NLRP3、caspase-1和ASC表达。通过免疫组织化学评估结肠嗜酸性粒细胞密度和claudin-1表达。在培养的细胞中测试了a β 对NLRP3信号传导和线粒体功能的影响。从六个月开始,SAMP8小鼠发生了认知障碍和粪便输出量减少。与SAMR1相比,SAMP8动物显示 :( 1) 体外结肠收缩受损; (2) 肠道AD相关蛋白,IL-1β,active-caspase-1表达和嗜酸性粒细胞密度增加; (3) 柠檬酸合酶活性和claudin-1表达降低。在THP-1细胞中,a β 促进IL-1β 释放,其在与caspase-1抑制剂或ASC-/-细胞孵育后被消除。A β 降低了THP-1细胞的线粒体功能。在SAMP8中,在整个大脑病理发展之前发生的肠道AD相关蛋白沉积,炎症和结肠兴奋性神经传递受损,可能会导致肠动力障碍并代表AD的前驱事件。

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