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  • 1.

    【2hr】Rheumatic Heart Disease

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    机译 风湿性心脏病
    摘要：Heart lesions of rheumatic heart disease (RHD) patients contain T-cell clones that recognize heart proteins and streptococcal M peptides. To functionally characterize heart-infiltrating T lymphocytes, we evaluated their cytokine profile, both directly in situ and in T-cell lines derived from the heart (HIL). Interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, and IL-10 expressions were characterized in 20 heart tissue infiltrates from 14 RHD patients by immunohistochemistry. IFN-γ-, TNF-α-, and IL-10-positive cells were consistently predominant, whereas IL-4 was scarce in the valves. In agreement with these data, the in vitro experiments, in which 13 HILs derived from heart samples of eight patients were stimulated with M5 protein and the immunodominant M5 (81-96) peptide, IL-4 was detected in HIL derived from the atrium (three of six) but not from the valve (zero of seven). IFN-γ and IL-10 production were detected in culture supernatants in 11 of 13 and 6 of 12 HILs, respectively. The predominant IFN-γ and TNF-α expression in the heart suggests that Th1-type cytokines could mediate RHD. Unlike in reversible myocardium inflammation, the significantly lower IL-4 expression in the valvular tissue (P = 0.02) may contribute to the progression of the RHD leading to permanent valvular damage (relative risk, 4.3; odds ratio, 15.8). The lack of IL-4 in vitro production by valve-derived HIL also emphasizes the more severe tissue destruction in valves observed in RHD.
  • 2.

    【2hr】Lack of the Growth Factor Midkine Enhances Survival against Cisplatin-Induced Renal Damage

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    机译 缺乏生长因子Midkine可以增强抵抗顺铂诱导的肾损伤的存活率
    摘要：Although cisplatin acts directly on proximal tubule epithelial cells and causes cell death, little is known regarding the biological significance of its secondary effects, such as inflammation. The growth factor midkine is highly expressed in the proximal tubule and exerts ambivalent activities as to cisplatin nephrotoxicity, ie, anti-apoptotic and chemotactic ones. Here we report that midkine-deficient mice show a significantly higher survival rate than wild-type mice. The levels of blood urea nitrogen and tubular degeneration and apoptosis were higher in wild-type mice despite the anti-apoptotic activity of midkine. We found that recruitment of neutrophils was more enhanced in wild-type mice, this being consistent with the chemotactic activity of midkine. Midkine expression in wild-type mice persisted for 24 hours, and then dramatically decreased. Preadministration of midkine anti-sense oligodeoxyribonucleotide to wild-type mice suppressed midkine expression, and consequently neutrophil infiltration. It is of note that neutrophil infiltration, apoptosis, and elevation of blood urea nitrogen became conspicuous sequentially, namely 1, 2, and 3 days after cisplatin administration, respectively. These findings suggest that early molecular events involving midkine induce inflammatory response and their circuits eventually enhance the death of the proximal tubule epithelial cells. The results indicate the crucial role of inflammation in cisplatin-induced renal damage, and provide a candidate molecular target for its prevention.
  • 3.

    【2hr】ADAM12 Is Selectively Overexpressed in Human Glioblastomas and Is Associated with Glioblastoma Cell Proliferation and Shedding of Heparin-Binding Epidermal Growth Factor

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    机译 ADAM12在人类胶质母细胞瘤中选择性过表达，并与胶质母细胞瘤细胞增殖和肝素结合表皮生长因子脱落有关。
    摘要：ADAMs (a disintegrin and metalloproteinases) are multifunctional molecules involved in cell-cell fusion, cell adhesion, membrane protein shedding, and proteolysis. In the present study, we examined the mRNA expression of 13 different ADAM species with putative metalloproteinase activity in human astrocytic tumors, nonneoplastic brain tissues, and other intracranial tumors by reverse transcriptase-polymerase chain reaction, and found that prototype membrane-anchored ADAM12 (ADAM12m) is predominantly expressed in glioblastomas. Real-time quantitative polymerase chain reaction indicated that the expression level of ADAM12m is remarkably at least 5.7-fold higher in glioblastomas (n = 16) than in nonneoplastic brain tissues (n = 6), low grade (n = 7) and anaplastic astrocytic tumors (n = 9) (P < 0.05 for each group), and intracranial neurinomas (n = 5) (P < 0.01). In situ hybridization showed that glioblastoma cells are responsible for the gene expression. By immunohistochemistry, ADAM12m was predominantly immunolocalized on the cell membranes of glioblastoma cells. Immunoblotting analysis demonstrated that ADAM12m is expressed as an activated N-glycosylated form of ∼90 kd in glioblastoma tissues. There was a direct correlation between the mRNA expression levels of ADAM12m and proliferative activity (MIB1-positive cell index) of gliomas (r = 0.791, P < 0.0001; n = 32). Protein bands consistent with the soluble form of heparin-binding epidermal growth factor, a substrate of ADAM12m, were observed by immunoblotting in glioblastoma samples with the ADAM12m expression, and inhibited by treatment with ADAM inhibitor of the glioblastomas. These data demonstrate for the first time that among the 13 different ADAM species, ADAM12m is highly expressed in human glioblastomas, and suggest the possibility that ADAM12m plays a role in the prominent proliferation of the glioblastomas through shedding of heparin-binding epidermal growth factor.
  • 4.

    【2hr】Loss of p53 Sensitizes Mice with a Mutation in Ccm1 (KRIT1) to Development of Cerebral Vascular Malformations

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    机译 p53的丢失会导致小鼠Ccm1（KRIT1）突变致脑血管畸形的发展。
    摘要：Cerebral cavernous malformations (CCM) consist of clusters of abnormally dilated blood vessels. Hemorrhaging of these lesions can cause seizures and lethal stroke. Three loci are associated with autosomal dominant CCM, and the causative genes have been identified for CCM1 and CCM2. We have generated mice with a targeted mutation of the Ccm1 gene, but an initial survey of 20 heterozygous mice failed to detect any cavernous malformations. To test the hypothesis that growth of cavernous malformations depends on somatic loss of heterozygosity at the Ccm1 locus, we bred animals that were heterozygous for the Ccm1 mutation and homozygous for loss of the tumor suppressor Trp53 (p53), which has been shown to increase the rate of somatic mutation. We observed vascular lesions in the brains of 55% of the double-mutant animals but none in littermates with other genotypes. Although the genetic evidence suggested somatic mutation of the wild-type Ccm1 allele, we were unable to demonstrate loss of heterozygosity by molecular methods. An alternative explanation is that p53 plays a direct role in formation of the vascular malformations. The striking similarity of the human and mouse lesions indicates that the Ccm1+/− Trp53−/− mice are an appropriate animal model of CCM.
  • 5.

    【2hr】PITX2 Gain-of-Function in Rieger Syndrome Eye Model

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    机译 PITX2在Rieger综合征眼模型中的功能获得
    摘要：The human autosomal-dominant disorder Axenfeld-Rieger syndrome presents with defects in development of the eyes, teeth, and umbilicus. The eye manifests with iris ruptures, irido-corneal adhesions, cloudy corneas, and glaucoma. Transcription factors such as PITX2 and FOXC1 have been found to carry point mutations, causing the disorder. However, for ∼40% of the cases, the pathogenesis is unknown. It has been reported that some mutations in PITX2 increase transactivation, whereas most mutations cause defects in DNA binding or transactivation. It is not known whether up-regulation of PITX2 activity can cause the disorder as well. Here we test this hypothesis directly by overexpressing PITX2A as a transgene in mouse corneal mesenchyme and iris, using keratocan-flanking sequences. The mice presented with corneal opacification, corneal hypertrophy, irido-corneal adhesions, and severely degenerated retina, resembling glaucoma. The corneal hypertrophy also resembles the corneal hypertrophy of Pitx2−/− mice. Control transgenic mice carrying point mutations T68P or K88E in PITX2A were normal. These findings indicate a novel pathogenetic mechanism in which excess corneal and iridal PITX2A cause glaucoma and anterior defects that closely resemble Axenfeld-Rieger syndrome.
  • 6.

    【2hr】Gender, Age, and Season at Immunization Uniquely Influence the Genetic Control of Susceptibility to Histopathological Lesions and Clinical Signs of Experimental Allergic Encephalomyelitis

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    机译 免疫接种的性别，年龄和季节会独特地影响对组织病理学病变的遗传控制以及实验性变应性脑脊髓炎的临床体征
    摘要：Multiple sclerosis (MS), the principal inflammatory demyelinating disease of the central nervous system (CNS), is believed to have an immunopathological etiology arising from gene-environment interactions. In this study, we examined the effect of sex, age, and season at immunization on the susceptibility of (B10.S × SJL/J) F2 intercross mice to experimental allergic encephalomyelitis (EAE), the foremost animal model of MS. Results of logistic regression analyses suggest that female mice were more likely to exhibit CNS lesions than male mice [odds ratio (OR) = 2.28 for brain lesions; OR = 2.37 for spinal cord (SC) lesions]. Although statistically significant associations were seen between brain and SC lesions and age at the time of injection or month of injection when examined separately; these associations disappeared when controlling for sex in multiple logistic regression analyses. These results suggest that the sex of the mouse is more important in influencing the development of brain and SC lesions than was either age or month of immunization. When examining clinical disease as the endpoint, the OR for the age at immunization is 1.04, indicating that the odds of being affected increase by 4% for each increasing week of age. When controlled for age, the OR for injection in the summer months (July through September) is 1.90, suggesting that the odds of being clinically affected are 90% greater for F2 intercross animals injected in the summercompared to those injected in the winter to spring months (February through May). In contrast to CNS lesions, the age and season at immunization significantly and independently influenced susceptibility to clinical EAE and did so equally in both males and females. Linkage analysis to eae5, the H2-linked locus controlling susceptibility to clinical disease, was performed using 6- to 12- and >12-week-old cohorts as well as summer and winter/spring cohorts of F2 mice. Significant linkage of clinical EAE to eae5 was observed with the 6- to 12-week-old and summer populations. In contrast, linkage of clinical EAE to eae5 was not detected with the >12-week-old and winter/spring populations. These results indicate that age and seasonal effects are capable of overriding eae5-dependent genetic control of susceptibility to clinical EAE and have significant implications for the genetics of MS.
  • 7.

    【2hr】Reversible Demyelination, Blood-Brain Barrier Breakdown, and Pronounced Neutrophil Recruitment Induced by Chronic IL-1 Expression in the Brain

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    机译 脑中慢性IL-1表达诱导的可逆脱髓鞘作用，血脑屏障破坏和明显的中性白细胞募集
    摘要：Interleukin-1β (IL-1) expression is associated with a spectrum of neuroinflammatory processes related to chronic neurodegenerative diseases. The single-bolus microinjection of IL-1 into the central nervous system (CNS) parenchyma gives rise to delayed and localized neutrophil recruitment, transient blood-brain barrier (BBB) breakdown, but no overt damage to CNS integrity. However, acute microinjections of IL-1 do not mimic the chronic IL-1 expression, which is a feature of many CNS diseases. To investigate the response of the CNS to chronic IL-1 expression, we injected a recombinant adenovirus expressing IL-1 into the striatum. At the peak of IL-1 expression (days 8 and 14 post-injection), there was a marked recruitment of neutrophils, vasodilatation, and breakdown of the BBB. Microglia and astrocyte activation was evident during the first 14 days post-injection. At days 8 and 14, extensive demyelination was observed but the number of neurons was not affected by any treatment. Finally, at 30 days, signs of inflammation were no longer present, there was evidence of tissue reorganization, the BBB was intact, and the process of remyelination was noticeable. In summary, our data show that chronic expression of IL-1, in contrast to its acute delivery, can reversibly damage CNS integrity and implicates this cytokine or downstream components as major mediators of demyelination in chronic inflammatory and demyelinating diseases.
  • 8.

    【2hr】Angiopoietin-1 Promotes Tumor Angiogenesis in a Rat Glioma Model

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    机译 Angiopoietin-1促进大鼠脑胶质瘤模型中的肿瘤血管生成。
    摘要：Angiopoietins have been implicated in playing an important role in blood vessel formation, remodeling, maturation, and maintenance. However, the role of angiopoietins in tumor angiogenesis remains uncertain. In this study, expression of human angiopoietin-1 (hAng-1) and angiopoietin (hAng-2) was amplified in the rat glioma cell line GS9L by stable transfection using an inducible tet-off system. Transfected cells were implanted intracerebrally into syngenic Fischer 344 rats. We demonstrated by means of magnetic resonance imaging that increased hAng-1 expression promoted a significant in vivo growth of intracerebral gliomas in rats. Overexpression of hAng-1 resulted in more numerous, more highly branched vessels, which were covered by pericytes. On the other hand, tumors derived from hAng-2-overexpressing cells were smaller than empty-plasmid control tumors. The tumor vasculature in these tumors was composed of aberrant small vascular cords, which were associated with few mural cells. Our results indicate that in the presence of hAng-1, tumors induce a more functional vascular network, which led to better tumor perfusion and growth. On the other hand, overexpression of hAng-2 led to less intact tumor vessels, inhibited capillary sprouting, and impaired tumor growth.
  • 9.

    【2hr】Roles and Regulation of Stat Family Transcription Factors in Human Breast Cancer

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    机译 Stat家族转录因子在人类乳腺癌中的作用和调控
    摘要：Stats (for signal transducers and activators of transcription) are a family of transcription factors that regulate cell growth and differentiation. Their activity is latent until phosphorylation by receptor-associated kinases. A sizable body of data from cell lines, mouse models, and human tissues now implicates these transcription factors in the oncogenesis of breast cancer. Because Stat activity is modulated by several posttranslational modifications and protein-protein interactions, these transcription factors are capable of integrating inputs from multiple signaling networks. Given this, the future utilization of Stats as prognostic markers and therapeutic targets in human breast cancer appears likely.
  • 10.

    【2hr】Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Can Induce Apoptosis in Subsets of Premalignant Cells

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    机译 肿瘤坏死因子相关的凋亡诱导配体可以诱导亚细胞分化前的细胞凋亡。
    摘要：During the transformation from a normal to a malignant cell, several mutations are required to bypass the pathways responsible for controlling proliferation. Premalignant cells have acquired some, but not all of these mutations and consequently have not yet attained a malignant phenotype characterized by tumor formation in vivo. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in malignant cells while sparing normal ones and is currently being considered as adjuvant therapy for various human malignancies. Whether TRAIL is effective in inducing apoptosis in premalignant cells is unclear, however. We studied the effect of TRAIL on two human premalignant cell lines the SV7tert and HA1E cells. Both cell lines had been immortalized by the addition of simian virus 40 large T antigen and the telomerase subunit hTERT, but had not been transformed into malignant cells. TRAIL initiated apoptosis by activating both the mitochondrial-independent and -dependent apoptotic pathways in both cell lines at relatively low doses whereas it had no effect on normal human pulmonary artery smooth muscle cells even at high doses. These results suggest that TRAIL can induce apoptosis in premalignant cells and suggests a novel therapy for the treatment of premalignant lesions in vivo.
  • 11.

    【2hr】Subcellular Topography of Neuronal Aβ Peptide in APPxPS1 Transgenic Mice

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    机译 APPxPS1转基因小鼠中神经元Aβ肽的亚细胞形貌
    摘要：In transgenic mice expressing human mutant β-amyloid precursor protein (APP) and mutant presenilin-1 (PS1), Aβ antibodies labeled granules, about 1 μm in diameter, in the perikaryon of neurons clustered in the isocortex, hippocampus, amygdala, thalamus, and brainstem. The granules were present before the onset of Aβ deposits; their number increased up to 9 months and decreased in 15-month-old animals. They were immunostained by antibodies against Aβ 40, Aβ 42, and APP C-terminal region. In double immunofluorescence experiments, the intracellular Aβ co-localized with lysosome markers and less frequently with MG160, a Golgi marker. Aβ accumulation correlated with an increased volume of lysosomes and Golgi apparatus, while the volume of endoplasmic reticulum and early endosomes did not change. Some granules were immunolabeled with an antibody against flotillin-1, a raft marker. At electron microscopy, Aβ, APP-C terminal, cathepsin D, and flotillin-1 epitopes were found in the lumen of multivesicular bodies. This study shows that Aβ peptide and APP C-terminal region accumulate in multivesicular bodies containing lysosomal enzymes, while APP N-terminus is excluded from them. Multivesicular bodies could secondarily liberate their content in the extracellular space as suggested by the association of cathepsin D with Aβ peptide in the extracellular space.
  • 12.

    【2hr】The Mannose-Binding Lectin-Pathway Is Involved in Complement Activation in the Course of Renal Ischemia-Reperfusion Injury

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    机译 甘露糖结合凝集素途径参与肾缺血-再灌注损伤过程中的补体激活。
    摘要：Ischemia-reperfusion (I/R) is an important cause of acute renal failure (ARF). The complement system appears to be essentially involved in I/R injury. However, via which pathway the complement system is activated and in particular whether the mannose-binding lectin (MBL)-pathway is activated is unclear. This tempted us to study the activation and regulation of the MBL-pathway in the course of experimental renal I/R injury and in clinical post-transplant ARF. Mice subjected to renal I/R displayed evident renal MBL-depositions, depending on the duration of warm ischemia, in the early reperfusion phase. Renal deposition of C3, C6 and C9 was observed in the later reperfusion phase. The deposition of MBL-A and -C completely co-localized with the late complement factor C6, showing that MBL is involved in complement activation in the course of renal I/R injury. Moreover, the degree of early MBL-deposition correlated with complement activation, neutrophil-influx, and organ-failure observed in the later reperfusion phase. In serum of mice subjected to renal I/R MBL-A, levels increased in contrast to MBL-C levels, which dropped evidently. In line, liver mRNA levels for MBL-A increased, whereas MBL-C levels decreased. Renal MBL mRNA levels rapidly dropped in the course of renal I/R. Finally, in human biopsies, MBL-depositions were observed early after transplantation of ischemically injured kidneys. In line with our experimental data, in ischemically injured grafts displaying post-transplant organ-failure extensive MBL depositions were observed in peritubular capillaries and tubular epithelial cells. In conclusion, in experimental renal I/R injury and clinical post-transplant ARF the MBL-pathway is activated, followed by activation of the complement system. These data indicate that the MBL-pathway is involved in ischemia-induced complement activation.
  • 13.

    【2hr】T-Cell Properties Determine Disease Site, Clinical Presentation, and Cellular Pathology of Experimental Autoimmune Encephalomyelitis

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    机译 T细胞特性决定实验性自身免疫性脑脊髓炎的疾病部位，临床表现和细胞病理
    摘要：Two distinct clinical phenotypes of experimental autoimmune encephalomyelitis are observed in BALB interferon-γ knockout mice immunized with encephalitogenic peptides of myelin basic protein. Conventional disease, characterized by ascending weakness and paralysis, occurs with greater frequency after immunizing with a peptide comprising residues 59 to 76. Axial-rotatory disease, characterized by uncontrolled axial rotation, occurs with greater frequency in mice immunized with a peptide corresponding to exon 2 of the full length 21.5-kd protein. The two clinical phenotypes are histologically distinguishable. Conventional disease is characterized by inflammation and demyelination primarily in spinal cord, whereas axial-rotatory disease involves inflammation and demyelination of lateral medullary areas of brain. Both types have infiltrates in which neutrophils are a predominating component. By isolating T cells and transferring disease to naïve recipients, we show here that the type of disease is determined entirely by the inducing T cell. Furthermore, studies using CXCR2 knockout recipients, unable to recruit neutrophils to inflammatory sites, show that although neutrophils are critical for some of these T cells to effect disease, there are also interferon-γ-deficient T cells that induce disease in the absence of both interferon-γ and neutrophils. These results highlight the multiplicity of T-cell-initiated effector pathways available for inflammation and demyelination.
  • 14.

    【2hr】Quantitative Gene Expression Profiling in Formalin-Fixed, Paraffin-Embedded Tissues Using Universal Bead Arrays

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    机译 使用通用磁珠阵列在福尔马林固定，石蜡包埋的组织中定量基因表达谱分析
    摘要：We recently developed a sensitive and flexible gene expression profiling system that is not dependent on an intact poly-A tail and showed that it could be used to analyze degraded RNA samples. We hypothesized that the DASL (cDNA-mediated annealing, selection, extension and ligation) assay might be suitable for the analysis of formalin-fixed, paraffin-embedded tissues, an important source of archival tissue material. We now show that, using the DASL assay system, highly reproducible tissue- and cancer-specific gene expression profiles can be obtained with as little as 50 ng of total RNA isolated from formalin-fixed tissues that had been stored from 1 to over 10 years. Further, tissue- and cancer-specific markers derived from previous genome-wide expression profiling studies of fresh-frozen samples were validated in the formalin-fixed samples. The DASL assay system should prove useful for high-throughput expression profiling of archived clinical samples.
  • 15.

    【2hr】α2-Macroglobulin: A Novel Cytochemical Marker Characterizing Preneoplastic and Neoplastic Rat Liver Lesions Negative for Hitherto Established Cytochemical Markers

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    机译 α2-巨球蛋白：一种新型的细胞化学标记，表征迄今建立的细胞化学标记为阴性的前肿瘤和肿瘤大鼠肝脏病变
    摘要：We tried to identify a novel marker characteristic for rat hepatocellular preneoplastic and neoplastic lesions, undetectable by well established cytochemical markers. Glutathione S-transferase placental (GST-P)-negative hepatocellular altered foci (HAF), hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC) were generated by two initiation-promotion models with N-nitrosodiethylamine (NDEN) and peroxisome proliferators, Wy-14,643 and clofibrate. Total RNAs isolated from laser-microdissected GST-P-negative HAF (amphophilic cell foci) and adjacent normal tissues were applied to microarray analysis. As a result, five up-regulated genes were identified, and further detailed examinations of the gene demonstrating most fluctuation, ie, that for α2-macroglobulin (α2M) were performed. In reverse transcriptase-polymerase chain reaction, α2M mRNA was overexpressed not only in amphophilic GST-P-negative HAF but also in amphophilic GST-P-negative HCA and HCC. In situ hybridization showed accumulation of α2M mRNA to be evenly distributed within GST-P-negative HAF (predominantly amphophilic cell foci). Distinctive immunohistochemical staining for α2M could be consistently demonstrated in GST-P-negative HAF, HCA, and HCC induced not only by peroxisome proliferators but also N-nitrosodiethylamine alone. Thus our findings suggest that α2M is an important novel cytochemical marker to identify hepatocellular preneoplastic and neoplastic lesions, particularly amphophilic cell foci, undetectable by established cytochemical markers and is tightly linked to rat hepatocarcinogenesis.
  • 16.

    【2hr】Induction of Inflammatory Mediators and Microglial Activation in Mice Transgenic for Mutant Human P301S Tau Protein

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    机译 突变型人P301S Tau蛋白转基因小鼠中炎症介导剂的诱导和小胶质细胞活化。
    摘要：Mice transgenic for human P301S tau protein exhibit many characteristics of the human tauopathies, including the formation of abundant filaments made of hyperphosphorylated tau protein and neurodegeneration leading to nerve cell loss. At 5 months of age, the pathological changes are most marked in brainstem and spinal cord. Here we show that these changes are accompanied by marked neuroinflammation. Many tau-positive nerve cells in brainstem and spinal cord were strongly immunoreactive for interleukin-1β and cyclooxygenase-2, indicating induction and overproduction of proinflammatory cytokines and enzymes. In parallel, numerous activated microglial cells were present throughout brain and spinal cord of transgenic mice, where they concentrated around tau-positive nerve cells. These findings suggest that inflammation may play a significant role in the events leading to neurodegeneration in the tauopathies and that anti-inflammatory compounds may have therapeutic potential.
  • 17.

    【2hr】The Role of Interleukin-1β in Direct and Toll-Like Receptor 4-Mediated Neutrophil Activation and Survival

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    机译 白细胞介素-1β在直接和类似受体的4介导的中性粒细胞活化和存活中的作用。
    摘要：The regulation of systemic and local neutrophil activation is crucial to the clearance of infections and the successful resolution of inflammation without progress to tissue damage or disseminated inflammatory reactions. Using purified lipopolysaccharide (pLPS) and highly purified neutrophils, we have previously shown that Toll-like receptor 4 signaling is a potent neutrophil activator, but a poor stimulator of survival. In the presence of peripheral blood mononuclear cells (PBMCs), however, pLPS becomes a potent neutrophil survival factor. Interleukin (IL)-1β has been identified as an important neutrophil activator and prosurvival cytokine, and is produced in abundance by LPS-stimulated PBMCs. We now show that IL-1β fails to activate highly purified neutrophils or enhance their survival, but in the presence of PBMCs, IL-1β induces neutrophil survival. We hypothesized that LPS-primed neutrophils might become responsive to IL-1β, but were unable to demonstrate this. Moreover, IL-1ra failed to prevent pLPS + PBMC-dependent neutrophil survival. In studies of IL-1R1−/− mice, we found that LPS was still able to mediate neutrophil survival, and neutrophil survival was enhanced by the addition of monocytic cells. Thus an important paradigm of neutrophil regulation needs to be viewed in the context of a cellular network in which actions of IL-1β on neutrophils are indirect and mediated by other cells.
  • 18.

    【2hr】Hypermethylation of Growth Arrest DNA Damage-Inducible Gene 45 β Promoter in Human Hepatocellular Carcinoma

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    机译 肝细胞癌中生长停滞DNA损伤诱导基因45β启动子的超甲基化
    摘要：Growth arrest DNA damage-inducible gene 45 β (GADD45β) has been known to regulate cell growth, apoptotic cell death, and cellular response to DNA damage. Down-regulation of GADD45β has been verified to be specific in hepatocellular cancer (HCC) and consistent with the p53 mutant, and degree of malignancy of HCC. This observation was further confirmed by eight HCC cell lines and paired human normal and HCC tumor tissues by Northern blot and immunohistochemistry. To better understand the transcription regulation, we cloned and characterized the active promoter region of GADD45β in luciferase-expressing vector. Using the luciferase assay, three nuclear factor-κB binding sites, one E2F-1 binding site, and one putative inhibition region were identified in the proximal promoter of GADD45β from −865/+6. Of interest, no marked putative binding sites could be identified in the inhibition region between −520/−470, which corresponds to CpG-rich region. The demethylating agent 5-Aza-dC was used and demonstrated restoration of the GADD45β expression in HepG2 in a dose-dependent manner. The methylation status in the promoter was further examined in one normal liver cell, eight HCC cell lines, eight HCC tissues, and five corresponding nonneoplastic liver tissues. Methylation-specific polymerase chain reaction and sequencing of the sodium bisulfite-treated DNA from HCC cell lines and HCC samples revealed a high percentage of hypermethylation of the CpG islands. Comparatively, the five nonneoplastic correspondent liver tissues demonstrated very low levels of methylation. To further understand the functional role of GADD45β under-expression in HCC the GADD45β cDNA constructed plasmid was transfected into HepG2 (p53 WT) and Hep3B (p53 null) cells. The transforming growth factor-β was assayed by enzyme-linked immunosorbent assay, which revealed a decrease to 40% in transfectant of HepG2, but no significant change in Hep3B transfectant. Whereas, Hep3B co-transfected with p53 and GADD45β demonstrated significantly reduced transforming growth factor-β. The colony formation was further examined and revealed a decrease in HepG2-GADD45β transfectant and Hep3B-p53/GADD45β co-transfectant. These findings suggested that methylation might play a crucial role in the epigenetic regulation of GADD45β in hepatocyte transformation that may be directed by p53 status. Thus, our results provided a deeper understanding of the molecular mechanism of GADD45β down-regulation in HCC.
  • 19.

    【2hr】Staying Connected

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    机译 保持联系
    摘要：
  • 20.

    【2hr】β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Increases Amyloid Deposition in Brain Parenchyma but Reduces Cerebrovascular Amyloid Angiopathy in Aging BACE × APP[V717I] Double-Transgenic Mice

    包量

    机译 β-位淀粉样蛋白前体蛋白裂解酶1增加BACE老化中脑实质的淀粉样蛋白沉积，但减少脑血管淀粉样血管病×APP [V717I]双转基因小鼠
    摘要：The generation of amyloid peptides (Aβ) from the amyloid precursor protein (APP) is initiated by β-secretase (BACE), whereas subsequent γ-secretase cleavage mediated by presenilin-1, produces Aβ peptides mainly of 40 or 42 amino acids long. In addition, alternative β′-cleavage of APP at position 11 of the amyloid sequence results in N-truncated Aβ(11-40/42) peptides, but the functional significance or pathological impact is unknown. Here we demonstrate that in the brain of BACE × APP[V717I] double-transgenic mice, amyloidogenic processing at both Asp1 and Glu11 is increased resulting in more and different Aβ species and APP C-terminal fragments. Pathologically, BACE significantly increased the number of diffuse and senile amyloid plaques in old double-transgenic mice. Unexpectedly, vascular amyloid deposition was dramatically lower in the same BACE × APP[V717I] double-transgenic mice, relative to sex- and age-matched APP[V717I] single-transgenic mice in the same genetic background. The tight inverse relation of vascular amyloid to the levels of the less soluble N-terminally truncated Aβ peptides is consistent with the hypothesis that vascular amyloid deposition depends on drainage of excess tissue Aβ. This provides biochemical evidence in vivo for the preferential contribution of N-truncated Aβ to parenchymal amyloid deposition in contrast to vascular amyloid pathology.
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