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Midkine accumulated in nucleolus of HepG2 cells involved in rRNA transcription  [cached]
Li-Cheng Dai, Jian-Zhong Shao, Li-Shan Min, Yong-Tao Xiao, Li-Xin Xiang, Zhi-Hong Ma
World Journal of Gastroenterology , 2008,
Abstract: AIM: To investigate the ultrastructural location of midkine (MK) in nucleolus and function corresponding to its location.METHODS: To investigate the ultrastructural location of MK in nucleolus with immunoelectronic microscopy. To study the role that MK plays in ribosomal biogenesis by real-time PCR. The effect of MK on anti-apoptotic activity of HepG2 cells was studied with FITC-conjugated annexin V and propidium iodide PI double staining through FACS assay.RESULTS: MK mainly localized in the granular component (GC), dense fibrillar component (DFC) and the border between the DFC and fibrillar center (FC). The production of 45S precursor rRNA level was decreased significantly in the presence of MK antisense oligonucleotide in the HepG2 cells. Furthermore, it was found that exogenous MK could protect HepG2 from apoptosis significantly.CONCLUSION: MK was constitutively translocated to the nucleolus of HepG2 cells, where it accumulated and mostly distributed at DFC, GC components and at the region between FC and DFC, MK played an important role in rRNA transcription, ribosome biogenesis, and cell proliferation in HepG2 cells. MK might serve as a molecular target for therapeutic intervention of human carcinomas.
Midkine inhibitors: application of a simple assay procedure to screening of inhibitory compounds
Takashi Matsui, Keiko Ichihara-Tanaka, Chen Lan, Hisako Muramatsu, Toshiharu Kondou, Chizuru Hirose, Sadatoshi Sakuma, Takashi Muramatsu
International Archives of Medicine , 2010, DOI: 10.1186/1755-7682-3-12
Abstract: We developed a simple assay for midkine activity based on midkine-dependent migration of osteblastic cells. Midkine inhibitors were searched as materials that inhibit this midkine activity. To develop peptides that inhibit midkine activity, we constructed models in which C-terminal half of midkine interacted with α4β1-integrin. Low molecular weight compounds which are expected to bind to midkine with high affinity were searched by in silico screening with the aid of Presto-X2 program.Among peptides in putative binding sites of midkine and the integrin, a peptide derived from β1-integrin and that derived from the first β sheet of the C-terminal half of midkine significantly inhibited midkine activity. Two low molecular weight compounds found by in silico screening exhibited no toxicity to target cells, but inhibited midkine activity. They are trifluoro compounds: one (PubChem 4603792) is 2-(2,6-dimethylpiperidin-1-yl)-4-thiophen-2-yl-6-(trifluoromethy)pyrimidine, and the other has a related structure.The assay procedure is helpful in screening midkine inhibitors. All reagents described here might become mother material to develop clinically effective midkine inhibitors.Midkine is a heparin-binding cytokine of molecular weight 13 kDa [1-3]. It enhances growth, survival and migration of various target cells. Midkine has around 50% sequence identity with pleiotrophin, and the two factors exhibit overlapping roles in many cases [1,4]. Midkine is also involved in initiation or progression of many pathological status, such as tumor invasion [5] rheumatoid arthritis [6], experimental autoimmune encephalitis [7], adhesion after surgery [8], neointima formation of the blood vessel [9], hypertension [10], and renal injury after ischemia [11], exposure to chemotherapeutic reagent [12] and diabetes [13]. Antisense oligonucleotides or siRNAs to midkine exhibit therapeutic effects in animal experiments concerning tumor growth [5,14-16], ischemic renal failure [17], neointima forma
Molecular Pathways Involved in Prostate Carcinogenesis: Insights from Public Microarray Datasets  [PDF]
Sarah C. Baetke, Michiel E. Adriaens, Renaud Seigneuric, Chris T. Evelo, Lars M. T. Eijssen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049831
Abstract: Background Prostate cancer is currently the most frequently diagnosed malignancy in men and the second leading cause of cancer-related deaths in industrialized countries. Worldwide, an increase in prostate cancer incidence is expected due to an increased life-expectancy, aging of the population and improved diagnosis. Although the specific underlying mechanisms of prostate carcinogenesis remain unknown, prostate cancer is thought to result from a combination of genetic and environmental factors altering key cellular processes. To elucidate these complex interactions and to contribute to the understanding of prostate cancer progression and metastasis, analysis of large scale gene expression studies using bioinformatics approaches is used to decipher regulation of core processes. Methodology/Principal Findings In this study, a standardized quality control procedure and statistical analysis (http://www.arrayanalysis.org/) were applied to multiple prostate cancer datasets retrieved from the ArrayExpress data repository and pathway analysis using PathVisio (http://www.pathvisio.org/) was performed. The results led to the identification of three core biological processes that are strongly affected during prostate carcinogenesis: cholesterol biosynthesis, the process of epithelial-to-mesenchymal transition and an increased metabolic activity. Conclusions This study illustrates how a standardized bioinformatics evaluation of existing microarray data and subsequent pathway analysis can quickly and cost-effectively provide essential information about important molecular pathways and cellular processes involved in prostate cancer development and disease progression. The presented results may assist in biomarker profiling and the development of novel treatment approaches.
Midkine as a factor to counteract the deposition of amyloid β-peptide plaques: in vitro analysis and examination in knockout mice
Hisako Muramatsu1, Katsunori Yokoi, Lan Chen, Keiko Ichihara-Tanaka, Terutoshi Kimura, Takashi Muramatsu
International Archives of Medicine , 2011, DOI: 10.1186/1755-7682-4-1
Abstract: A surface plasmon assay was performed to determine the affinity of midkine for amyloid β-peptide. The deposition of amyloid β-peptide was compared in the brain of wild-type and midkine-deficient mice. An effect of midkine to microglias was examined by cell migration assay.Midkine bound to amyloid β-peptide with the affinity of 160 nM. The C-terminal half bound to the peptide more strongly than the N-terminal half, and heparin inhibited midkine from binding to the peptide. Pleiotrophin, which has about 50% sequence identity with midkine also bound to amyloid β-peptide. The deposition of amyloid β-peptide plaques in the cortex and hippocampus was more intense in 15-month-old midkine-deficient mice, compared to the corresponding wild-type mice. Midkine promoted migration of microglias in culture.These results are consistent with the view that midkine attenuates the deposition of amyloid β-peptide plaques, and thus progression of Alzheimer's disease, by direct binding and also by promoting migration of microglias.An accumulation of amyloid β-peptide (Aβ) in plaques in brain tissue has been proposed to be the primary cause of the neurodegeneration in patients with Alzheimer's disease [1,2]. This view is supported by findings that anti-Aβ antibodies prevent or reverse the disease in mouse models of Alzheimer's disease [1,3,4], although clinical trials of anti- Aβ antibodies did not give expected results [5,6]. Therefore, factors affecting the accumulation of Aβ plaques in brain tissue are important to the treatment and prevention of Alzheimer's disease. This paper primarily examines the role of midkine, a heparin-binding cytokine [7-9], in the deposition of Aβ plaques in the mouse brain.Midkine promotes neurite outgrowth [10], the survival of various cells including neurons [11-13] and the migration of inflammatory leukocytes [14,15] and neurons [16]. Midkine is involved in pathogenesis of malignant tumors [17] and diseases with immunological backgrounds [14,15,18-20] as
HDAC Up-Regulation in Early Colon Field Carcinogenesis Is Involved in Cell Tumorigenicity through Regulation of Chromatin Structure  [PDF]
Yolanda Stypula-Cyrus, Dhwanil Damania, Dhananjay P. Kunte, Mart Dela Cruz, Hariharan Subramanian, Hemant K. Roy, Vadim Backman
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064600
Abstract: Normal cell function is dependent on the proper maintenance of chromatin structure. Regulation of chromatin structure is controlled by histone modifications that directly influence chromatin architecture and genome function. Specifically, the histone deacetylase (HDAC) family of proteins modulate chromatin compaction and are commonly dysregulated in many tumors, including colorectal cancer (CRC). However, the role of HDAC proteins in early colorectal carcinogenesis has not been previously reported. We found HDAC1, HDAC2, HDAC3, HDAC5, and HDAC7 all to be up-regulated in the field of human CRC. Furthermore, we observed that HDAC2 up-regulation is one of the earliest events in CRC carcinogenesis and observed this in human field carcinogenesis, the azoxymethane-treated rat model, and in more aggressive colon cancer cell lines. The universality of HDAC2 up-regulation suggests that HDAC2 up-regulation is a novel and important early event in CRC, which may serve as a biomarker. HDAC inhibitors (HDACIs) interfere with tumorigenic HDAC activity; however, the precise mechanisms involved in this process remain to be elucidated. We confirmed that HDAC inhibition by valproic acid (VPA) targeted the more aggressive cell line. Using nuclease digestion assays and transmission electron microscopy imaging, we observed that VPA treatment induced greater changes in chromatin structure in the more aggressive cell line. Furthermore, we used the novel imaging technique partial wave spectroscopy (PWS) to quantify nanoscale alterations in chromatin. We noted that the PWS results are consistent with the biological assays, indicating a greater effect of VPA treatment in the more aggressive cell type. Together, these results demonstrate the importance of HDAC activity in early carcinogenic events and the unique role of higher-order chromatin structure in determining cell tumorigenicity.
Correlated fragile site expression allows the identification of candidate fragile genes involved in immunity and associated with carcinogenesis  [PDF]
A. Re,D. Cora,A. M. Puliti,M. Caselle,I. Sbrana
Quantitative Biology , 2006,
Abstract: Common fragile sites (cfs) are specific regions in the human genome that are particularly prone to genomic instability under conditions of replicative stress. Several investigations support the view that common fragile sites play a role in carcinogenesis. We discuss a genome-wide approach based on graph theory and Gene Ontology vocabulary for the functional characterization of common fragile sites and for the identification of genes that contribute to tumour cell biology. CFS were assembled in a network based on a simple measure of correlation among common fragile site patterns of expression. By applying robust measurements to capture in quantitative terms the non triviality of the network, we identified several topological features clearly indicating departure from the Erdos-Renyi random graph model. The most important outcome was the presence of an unexpected large connected component far below the percolation threshold. Most of the best characterized common fragile sites belonged to this connected component. By filtering this connected component with Gene Ontology, statistically significant shared functional features were detected. Common fragile sites were found to be enriched for genes associated to the immune response and to mechanisms involved in tumour progression such as extracellular space remodeling and angiogenesis. Our results support the hypothesis that fragile sites serve a function; we propose that fragility is linked to a coordinated regulation of fragile genes expression.
Structure of the nucleoli in domestic cattle spermatocytes  [cached]
Katarzyna Andraszek,El?bieta Smalec
Folia Histochemica et Cytobiologica , 2012, DOI: 10.5603/15543
Abstract: The work was aimed at determining the number and morphology of nucleoli in the prophase of the first meiotic division in domestic cattle males. The use of AgNO3 staining, commonly applied in cytogenetics for the identification of nucleolar organiser regions, made it possible to identify nucleoli in first-order spermatocytes. One nucleolus was identified in each analysed cell. Considerable morphological differentiation of the nucleoli during the prophase of the first meiotic division, particularly in leptotene, unobserved in other farm animal species, was noticed. Dark-hued grain-like structures were found within the disintegrating nucleoli, corresponding approximately or exactly to the number of the nucleolar organiser regions in the domestic cattle karyotype. Dark areas were identified in the selected prometaphase chromosomes. Their number corresponded with the number of active NORs defined in the domestic cattle karyotype.
Chemical carcinogenesis
Oliveira, Paula A.;Cola?o, Aura;Chaves, Raquel;Guedes-Pinto, Henrique;De-La-Cruz P., Luis F.;Lopes, Carlos;
Anais da Academia Brasileira de Ciências , 2007, DOI: 10.1590/S0001-37652007000400004
Abstract: the use of chemical compounds benefits society in a number of ways. pesticides, for instance, enable foodstuffs to be produced in sufficient quantities to satisfy the needs of millions of people, a condition that has led to an increase in levels of life expectancy. yet, at times, these benefits are offset by certain disadvantages, notably the toxic side effects of the chemical compounds used. exposure to these compounds can have varying effects, ranging from instant death to a gradual process of chemical carcinogenesis. there are three stages involved in chemical carcinogenesis. these are defined as initiation, promotion and progression. each of these stages is characterised by morphological and biochemical modifications and result from genetic and/or epigenetic alterations. these genetic modifications include: mutations in genes that control cell proliferation, cell death and dna repair - i.e. mutations in proto-oncogenes and tumour suppressing genes. the epigenetic factors, also considered as being non-genetic in character, can also contribute to carcinogenesis via epigenetic mechanisms which silence gene expression. the control of responses to carcinogenesis through the application of several chemical, biochemical and biological techniques facilitates the identification of those basic mechanisms involved in neoplasic development. experimental assays with laboratory animals, epidemiological studies and quick tests enable the identification of carcinogenic compounds, the dissection of many aspects of carcinogenesis, and the establishment of effective strategies to prevent the cancer which results from exposure to chemicals.
Are nucleoli participating in programmed cell death
Karel Smetana
Journal of Applied Biomedicine , 2003,
Abstract: Despite numerous publications on nucleoli, their participation in terminal maturation andprogrammed cell death have not been studied extensively. On the other hand, some observationsclearly indicate that terminal maturation and programmed cell death are accompanied by markednucleolar changes which reflect the cessation of nucleolar biosynthetic activities. In addition,nucleolar changes in the course of terminal maturation may precede programmed cell death.
Number of nucleoli in diploids and polyploids of the genus Achillea L.
Janina D?browska
Acta Societatis Botanicorum Poloniae , 1989, DOI: 10.5586/asbp.1989.041
Abstract: Nucleoli were counted in 9228 interphase nuclei of the apical root meristem of 40 Achillea L. taxa (di-, tetra-. hexa- and octoploids). It was established that the distribution of nucleoli number in an interphase nucleus can be used as a rough practical indicator to distinguish between diploids and polyploids. The highest number of nucleoli (12) was found in an octoploid Achillea pannonica, but only in a small percentage of the nuclei (0.3% out of 283 nuclei).
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