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Jiang X, Zhang H, Zhang H, Wang F, Wang X, Ding T, Zhang X, Wang T. Microcystin-LR-Induced Interaction between M2 Tumor-Associated Macrophage and Colorectal Cancer Cell Promotes Colorectal Cancer Cell Migration through Regulating the Expression of TGF-β1 and CST3. Int J Mol Sci 2023; 24:10527. [PMID: 37445705 DOI: 10.3390/ijms241310527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/08/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
Microcystin-LR (MC-LR) is a toxic secondary metabolite produced by cyanobacteria that has been demonstrated to promote colorectal cancer (CRC). However, the mechanism by which MC-LR enhances CRC in the tumor microenvironment (TME) is poorly understood. To elucidate its role in TME, a co-culture system was established using CRC cells and M2 macrophages in a Transwell chamber. The study found that MC-LR promotes CRC cell migration by upregulating TGF-β1 expression and secretion in M2 macrophages and downregulating CST3 in CRC cells. Neutralizing TGF-β1 increased CST3 expression in CRC cells, while overexpressing CST3 in CRC cells suppressed TGF-β1 expression in M2 macrophages, both of which weakened MC-LR-induced cellular motility in the co-culture system. In vivo, the mice in the MC-LR/AOM/DSS group had more tumor nodules, deeper tumor invasion, and higher M2 macrophage infiltration compared to the AOM/DSS group, and the expression of TGF-β1 and CST3 in tumors was consistent with the cellular level. Overall, this study provides insights into the regulatory mechanism of MC-LR on TME, revealing that MC-LR upregulates the expression and secretion of TGF-β1 in M2 macrophages, which in turn inhibits the expression of CST3 in CRC cells to promote migration.
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Affiliation(s)
- Xinying Jiang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China
| | - Hailing Zhang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China
| | - Hengshuo Zhang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China
| | - Fan Wang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China
| | - Xiaochang Wang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China
| | - Tong Ding
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China
| | - Xuxiang Zhang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Xianlin Campus, Nanjing University, Nanjing 210023, China
| | - Ting Wang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China
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Xin C, Xie J, Fan H, Sun X, Shi B. Association Between Serum Cystatin C and Thyroid Diseases: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2021; 12:766516. [PMID: 34867811 PMCID: PMC8639734 DOI: 10.3389/fendo.2021.766516] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 10/23/2021] [Indexed: 12/03/2022] Open
Abstract
Background Cystatin C (CysC) is often used to diagnose and monitor renal diseases. Although some studies have investigated the association between serum CysC levels and thyroid diseases, their reported results were inconsistent. Therefore, the relationship between CysC levels and thyroid diseases remains controversial. Aim This meta-analysis aimed to statistically evaluate serum CysC levels in patients with thyroid diseases. Methods A literature search was conducted using the PubMed, Web of Science, Embase, EBSCO, and Wiley Online Library databases. The following search terms were used for the title or abstract: "Cystatin C" or "CysC" in combination with the terms "thyroid disease", "thyroid function", "hypothyroidism", or "hyperthyroidism". The results of the systematic analysis were presented as standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs). Results Eleven articles (1,265 cases and 894 controls) were included in the meta-analysis. The results of the meta-analysis showed that the serum CysC levels of patients with hyperthyroidism were significantly higher than those of the controls (SMD: 1.79, 95% CI [1.34, 2.25]), and the serum CysC levels of patients with hypothyroidism were significantly lower than those of the controls (SMD -0.59, 95% CI [-0.82, -0.36]). Moreover, the treatment of thyroid diseases significantly affected serum CysC levels. Conclusions To the best of our knowledge, this meta-analysis is the first to evaluate serum CysC levels in patients with thyroid diseases. Our findings suggest that thyroid function affects serum CysC levels and that serum CysC may be an effective marker for monitoring thyroid diseases. Systematic Review Registration PROSPERO [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=258022], identifier CRD42021258022].
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Affiliation(s)
- Caihong Xin
- Department of Endocrinology and Metabolism, Fourth People’s Hospital of Shenyang, Shenyang, China
| | - Jing Xie
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Huaying Fan
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xin Sun
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Bimin Shi
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Soochow University, Suzhou, China
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Woods L, Morgan N, Zhao X, Dean W, Perez-Garcia V, Hemberger M. Epigenetic changes occur at decidualisation genes as a function of reproductive ageing in mice. Development 2020; 147:147/6/dev185629. [PMID: 32184271 DOI: 10.1242/dev.185629] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 02/07/2020] [Indexed: 12/27/2022]
Abstract
Reproductive decline in older female mice can be attributed to a failure of the uterus to decidualise in response to steroid hormones. Here, we show that normal decidualisation is associated with significant epigenetic changes. Notably, we identify a cohort of differentially methylated regions (DMRs), most of which gain DNA methylation between the early and late stages of decidualisation. These DMRs are enriched at progesterone-responsive gene loci that are essential for reproductive function. In female mice nearing the end of their reproductive lifespan, DNA methylation fidelity is lost at a number of CpG islands (CGIs) resulting in CGI hypermethylation at key decidualisation genes. Importantly, this hypermethylated state correlates with the failure of the corresponding genes to become transcriptionally upregulated during the implantation window. Thus, age-associated DNA methylation changes may underlie the decidualisation defects that are a common occurrence in older females. Alterations to the epigenome of uterine cells may therefore contribute significantly to the reproductive decline associated with advanced maternal age.
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Affiliation(s)
- Laura Woods
- Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.,Centre for Trophoblast Research, University of Cambridge, Tennis Court Road, Cambridge CB2 3DY, UK
| | - Natasha Morgan
- Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.,Centre for Trophoblast Research, University of Cambridge, Tennis Court Road, Cambridge CB2 3DY, UK
| | - Xiang Zhao
- Dept. of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Wendy Dean
- Dept. of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.,Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.,Dept. of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Vicente Perez-Garcia
- Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.,Centre for Trophoblast Research, University of Cambridge, Tennis Court Road, Cambridge CB2 3DY, UK
| | - Myriam Hemberger
- Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK .,Centre for Trophoblast Research, University of Cambridge, Tennis Court Road, Cambridge CB2 3DY, UK.,Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.,Dept. of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.,Dept. of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary AB T2N 4N1, Canada
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4
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Park YS, Kim Y, Kim HY, Ahn KH, Cho GJ, Hong SC, Oh MJ, Kim HJ. Serum sFlt-1, cystatin C and cathepsin B are potential severity markers in preeclampsia: a pilot study. Arch Gynecol Obstet 2020; 301:955-962. [PMID: 32140809 DOI: 10.1007/s00404-020-05478-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Accepted: 02/25/2020] [Indexed: 12/15/2022]
Abstract
PURPOSE Preeclampsia is associated with abnormal invasion of the trophoblast through decidua and subsequently altered remodeling of the maternal spiral arteries and endothelial dysfunction. This phenomenon is explained by the dysregulation of various kinds of vascular factors and proteases. The purpose of this study was to compare the circulating levels of sFlt-1, cathepsin B, and cystatin C in preeclamptic and normotensive pregnancies. STUDY DESIGN Sixty-two pregnant women were enrolled in this prospective study. Twenty women were preeclamptic and 42 were normotensive. Serum levels of sFlt-1, cathepsin B, and cystatin C were measured using an enzyme-linked immunosorbent assay kit. RESULTS Circulating levels of sFlt-1, cathepsin B, and cystatin C were significantly higher in preeclamptic than in normotensive pregnant women (p < 0.001; p = 0.017; p = 0.003). Preeclamptic women with severe features demonstrated significantly higher levels of cathepsin B (p = 0.05). Serum sFlt-1 and cystatin C levels were positively correlated with elevated systolic and diastolic blood pressure. The levels of cathepsin B were positively correlated with alanine and aspartate aminotransferase. The amount of 24 h proteinuria was positively, but non-significantly correlated with sFlt-1 and cystatin C. CONCLUSIONS In addition to sFlt-1 levels, the serum levels of cathepsin B and cystatin C significantly change when preeclampsia develops. These markers are associated with severity markers of elevated blood pressure and liver injury in preeclampsia.
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Affiliation(s)
- Ye Sul Park
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Yezi Kim
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Ho Yeon Kim
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Republic of Korea.
| | - Ki-Hoon Ahn
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Geum Joon Cho
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Soon-Cheol Hong
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Min-Jeong Oh
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hai-Joong Kim
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Republic of Korea
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5
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Woods L, Perez-Garcia V, Kieckbusch J, Wang X, DeMayo F, Colucci F, Hemberger M. Decidualisation and placentation defects are a major cause of age-related reproductive decline. Nat Commun 2017; 8:352. [PMID: 28874785 PMCID: PMC5585348 DOI: 10.1038/s41467-017-00308-x] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 06/20/2017] [Indexed: 12/19/2022] Open
Abstract
Mammalian reproductive performance declines rapidly with advanced maternal age. This effect is largely attributed to the exponential increase in chromosome segregation errors in the oocyte with age. Yet many pregnancy complications and birth defects that become more frequent in older mothers, in both humans and mice, occur in the absence of karyotypic abnormalities. Here, we report that abnormal embryonic development in aged female mice is associated with severe placentation defects, which result from major deficits in the decidualisation response of the uterine stroma. This problem is rooted in a blunted hormonal responsiveness of the ageing uterus. Importantly, a young uterine environment can restore normal placental as well as embryonic development. Our data highlight the pivotal, albeit under-appreciated, impact of maternal age on uterine adaptability to pregnancy as major contributor to the decline in reproductive success in older females.Advanced maternal age has been associated with lower reproductive success and higher risk of pregnancy complications. Here the authors show that maternal ageing-related embryonic abnormalities in mouse are caused by decidualisation and placentation defects that can be rescued by transferring the embryo from an old to a young uterus.
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Affiliation(s)
- Laura Woods
- Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK
- Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK
| | - Vicente Perez-Garcia
- Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK
- Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK
| | - Jens Kieckbusch
- Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Box 111, Hills Road, Cambridge, CB2 0SP, UK
| | - Xiaoqiu Wang
- Reproductive and Developmental Biology Laboratory, NIEHS, Research Triangle Park, Durham, NC, 27709, USA
| | - Francesco DeMayo
- Reproductive and Developmental Biology Laboratory, NIEHS, Research Triangle Park, Durham, NC, 27709, USA
| | - Francesco Colucci
- Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Box 111, Hills Road, Cambridge, CB2 0SP, UK
| | - Myriam Hemberger
- Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
- Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
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Borbely AU, Fontenele-Neto JD, Vidsiunas AK, Gomes SZ, Hoshida MS, de Oliveira SF, Bevilacqua E. Ectoplacental Cone Induces Resistance to Apoptosis in High Doses of Interferon (IFN)-γ-Treated Decidual Cells. Am J Reprod Immunol 2011; 67:73-83. [DOI: 10.1111/j.1600-0897.2011.01060.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Miura S, Shukunami C, Mitsui K, Kondo J, Hiraki Y. Localization of chondromodulin-I at the feto-maternal interface and its inhibitory actions on trophoblast invasion in vitro. BMC Cell Biol 2011; 12:34. [PMID: 21849085 PMCID: PMC3171719 DOI: 10.1186/1471-2121-12-34] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Accepted: 08/18/2011] [Indexed: 12/02/2022] Open
Abstract
Background Chondromodulin-I (ChM-I) is an anti-angiogenic glycoprotein that is specifically localized at the extracellular matrix of the avascular mesenchyme including cartilage and cardiac valves. In this study, we characterized the expression pattern of ChM-I during early pregnancy in mice in vivo and its effect on invasion of trophoblastic cells into Matrigel in vitro. Results Northern blot analysis clearly indicated that ChM-I transcripts were expressed in the pregnant mouse uterus at 6.5-9.5 days post coitum. In situ hybridization and immunohistochemistry revealed that ChM-I was localized to the mature decidua surrounding the matrix metalloproteinase-9 (MMP-9)-expressing trophoblasts. Consistent with this observation, the expression of ChM-I mRNA was induced in decidualizing endometrial stromal cells in vitro, in response to estradiol and progesterone. Recombinant human ChM-I (rhChM-I) markedly inhibited the invasion through Matrigel as well as the chemotactic migration of rat Rcho-1 trophoblast cells in a manner independent of MMP activation. Conclusions This study demonstrates the inhibitory action of ChM-I on trophoblast migration and invasion, implying the potential role of the ChM-I expression in decidual cells for the regulated tissue remodeling and angiogenesis at feto-maternal interface.
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Affiliation(s)
- Shigenori Miura
- Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
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8
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Amarante-Paffaro A, Hoshida M, Yokota S, Gonçalves C, Joazeiro P, Bevilacqua E, Yamada A. Localization of Cathepsins D and B at the Maternal-Fetal Interface and the Invasiveness of the Trophoblast during the Postimplantation Period in the Mouse. Cells Tissues Organs 2011; 193:417-25. [DOI: 10.1159/000320546] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2010] [Indexed: 01/22/2023] Open
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9
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Kotajima N, Yanagawa Y, Aoki T, Tsunekawa K, Morimura T, Ogiwara T, Nara M, Murakami M. Influence of thyroid hormones and transforming growth factor-β1 on cystatin C concentrations. J Int Med Res 2010; 38:1365-73. [PMID: 20926009 DOI: 10.1177/147323001003800418] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Serum cystatin C concentrations are reported to increase in the hyperthyroid state. Serum concentrations of cystatin C and transforming growth factor-β1 (TGF-β1) were measured in patients with thyroid dysfunction, and the effects of 3,5,3'-tri-iodothyronine (T(3)) and TGF-β1 on cystatin C production in human hepatoblastoma (Hep G2) cells were studied. Serum concentrations of cystatin C and TGF-β1 were significantly higher in patients with Graves' disease compared with control subjects. Significantly positive correlations were observed between thyroid hormones and cystatin C, thyroid hormones and TGF-β1, and TGF-β1 and cystatin C in patients with thyroid dysfunction. Serum concentrations of cystatin C and TGF-β1 decreased after treatment for hyperthyroidism. Cystatin C mRNA levels and cystatin C secretion were increased by T(3) and TGF-β1 in cultured Hep G2 cells. These results suggest that serum cystatin C concentrations increase in patients with hyperthyroidism. The mechanisms for this may involve elevation of serum TGF-β1 levels and the stimulatory effects of T(3) and TGF-β1 on cystatin C production.
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Affiliation(s)
- N Kotajima
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
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10
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Herington JL, Bany BM. Do molecular signals from the conceptus influence endometrium decidualization in rodents? JOURNAL OF EXPERIMENTAL ZOOLOGY. PART B, MOLECULAR AND DEVELOPMENTAL EVOLUTION 2009; 312:797-816. [PMID: 19551814 PMCID: PMC2844778 DOI: 10.1002/jez.b.21308] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
A critical period in establishing pregnancy occurs after the onset of implantation but before placental development. Evidence strongly suggests that abnormalities occurring during this period can result in pregnancy termination or in pre-eclampsia; the latter may lead to small-for-gestational-weight offspring that are likely to be unhealthy. Clearly, events occurring in the endometrium during the implantation process are crucial for proper fetal development and for optimal offspring health. In several mammalian species bi-directional communication between the conceptus and endometrium during implantation is required for successful pregnancy. Although different implantation and placentation modes occur in different mammalian species, common aspects of this bi-directional signaling may exist. The molecular signals from the trophoblast cells of the conceptus, which direct endometrial changes during implantation progression, are well known in some nonrodent species. Currently, we know little about such signaling in rodents during implantation progression, when the endometrium undergoes decidualization. This review focuses on data that support the hypothesis that paracrine signals from the rodent conceptus influence decidualization. Where possible, these findings are compared and contrasted with information currently known in other species that exhibit different implantation modes.
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Affiliation(s)
- Jennifer L. Herington
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois, USA
| | - Brent M. Bany
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois, USA
- Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, Carbondale, Illinois, USA,
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Abstract
Low molecular-mass plasma proteins play a key role in health and disease. Cystatin C is an endogenous cysteine proteinase inhibitor belonging to the type 2 cystatin superfamily. The mature, active form of human cystatin C is a single non-glycosylated polypeptide chain consisting of 120 amino acid residues, with a molecular mass of 13,343-13,359 Da, and containing four characteristic disulfide-paired cysteine residues. Human cystatin C is encoded by the CST3 gene, ubiquitously expressed at moderate levels. Cystatin C monomer is present in all human body fluids; it is preferentially abundant in cerebrospinal fluid, seminal plasma, and milk. Cystatin C L68Q variant is an amyloid fibril-forming protein with a high tendency to dimerize. It forms self-aggregates with massive amyloid deposits in the brain arteries of young adults, leading to lethal cerebral hemorrhage. The main catabolic site of cystatin C is the kidney: more than 99% of the protein is cleared from the circulation by glomerular ultrafiltration and tubular reabsorption. The diagnostic value of cystatin C as a marker of kidney dysfunction has been extensively investigated in multiple clinical studies on adults, children, and in the elderly. In almost all the clinical studies, cystatin C demonstrated a better diagnostic accuracy than serum creatinine in discriminating normal from impaired kidney function, but controversial results have been obtained by comparing this protein with other indices of kidney disease, especially serum creatinine-based equations. In this review, we present and discuss most of the available data from the literature, critically reviewing conclusions and suggestions for the use of cystatin C in clinical practice. Despite the multitude of clinical data in the literature, cystatin C has not been widely used, perhaps because of a combination of factors, such as a general diffidence among clinicians, the absence of definitive cut-off values, conflicting results in clinical studies, no clear evidence on when and how to request the test, the poor commutability of results, and no accurate examination of costs and of its routine use in a stat laboratory.
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Affiliation(s)
- Michele Mussap
- Department of Laboratory Medicine, University-Hospital of Padua, Padua, Italy
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12
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Sharma N, Kaur J, Xu H, Zur Nieden N, Rancourt D. Characterization of secretory leukocyte protease inhibitor as an inhibitor of implantation serine proteinases. Mol Reprod Dev 2008; 75:1136-42. [PMID: 18163438 DOI: 10.1002/mrd.20855] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
We have recently identified and characterized two implantation serine proteinase genes, ISP1 and ISP2, which give rise to a dimeric proteinase, ISP that facilitates embryo invasion during peri-implantation period. As many proteinases have cognate serpins that regulate their proteolytic activity, we have been investigating anti-tryptases, expressed during this window of implantation. Here, we report the differential expression of secretory leukocyte protease inhibitor (SLPI) in uterine endometrium around the implantation period. The co-localization of SLPI and ISP suggests the possibility that SLPI is an ISP serpin and that expression of SLPI may lead to a reduction in ISP activity. The expression of SLPI is down regulated during the window of embryo-uterine receptivity. Our results are consistent with a model suggesting that the drop in SLPI expression may help to refine the opening of the window of implantation, by allowing the proteolytic activity of embryo invasive serine proteinases such as the ISPs.
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Affiliation(s)
- Navneet Sharma
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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Sireesha G, Mason R, Hassanein M, Tonack S, Navarrete Santos A, Fischer B, Seshagiri P. Role of cathepsins in blastocyst hatching in the golden hamster. Mol Hum Reprod 2008; 14:337-46. [DOI: 10.1093/molehr/gan026] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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14
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Yetkin E, Acikgoz N, Sivri N, Tekin GO, Yagmur J, Aksoy Y, Turhan H. Increased plasma levels of cystatin C and transforming growth factor-beta1 in patients with coronary artery ectasia: can there be a potential interaction between cystatin C and transforming growth factor-beta1. Coron Artery Dis 2007; 18:211-4. [PMID: 17429295 DOI: 10.1097/mca.0b013e328087bd98] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Cystatin C, known as an inhibitor of the cathepsin family of cysteine proteases, has been evaluated in several cardiovascular disorders such as atherosclerosis and acute myocardial infarction. The potential interaction between transforming growth factor-beta1 and cystatin C has also been demonstrated in some cell types. Accordingly, we aimed to compare the plasma levels of cystatin C and transforming growth factor-beta1 in patients with coronary artery ectasia coexisting with coronary artery disease and those with coronary artery disease alone. Thirty-nine patients with coronary artery ectasia and coronary artery disease and 35 age and sex-matched patients with coronary artery disease alone were prospectively enrolled in the study. Blood samples of all patients and control participants for measuring plasma cystatin C and transforming growth factor-beta1 levels were drawn>or=24 h after the coronary angiography. Cystatin C concentrations in plasma were measured by latex-enhanced reagent on a Behring Nephelometer II. Plasma levels of transforming growth factor-beta1 were measured by using transforming growth factor-beta1 enzyme-linked immunosorbent assay kit (BioSource International, Inc., Camarillo, California, USA). Plasma level of cystatin C was significantly higher in patients with coronary artery ectasia+coronary artery disease than in patients with coronary artery disease alone (1.05+/-0.30 mg/dl vs. 0.92+/-0.18 mg/mdl, P=0.025, respectively). Transforming growth factor-beta1 was also found to be significantly higher in patients with coronary artery ectasia+coronary artery disease compared with those with coronary artery disease (2.47+/-0.43 vs. 2.22+/-0.43 pg/ml, P=0.02, respectively). The plasma level of cystatin C was significantly but weakly correlated with that of transforming growth factor-beta1 (r=0.217 P=0.02). We conclude that plasma levels of cystatin C and transforming growth factor-beta1 are significantly higher in patients with combined coronary artery ectasia and coronary artery disease than in those with coronary artery disease. Correlation between transforming growth factor-beta1 and cystatin C may also suggest that pathogenesis of coronary artery ectasia might have some different pathways from atherosclerosis with respect to the regulation of extracellular matrix remodeling. Therefore, the role of cystatin in the pathogenesis of coronary artery ectasia and its potential interaction with transforming growth factor-beta1 should be evaluated in further studies.
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Affiliation(s)
- Ertan Yetkin
- Inonu University Faculty of Medicine, Department of Cardiology, Malatya, Turkey.
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Gianazza E, Wait R, Begum S, Eberini I, Campagnoli M, Labò S, Galliano M. Mapping the 5–50-kDa fraction of human amniotic fluid proteins by 2-DE and ESI-MS. Proteomics Clin Appl 2007; 1:167-75. [DOI: 10.1002/prca.200600543] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Vadigepalli R, Hao H, Miller GM, Liu H, Schwaber JS. Epidermal growth factor receptor-induced circadian-time-dependent gene regulation in suprachiasmatic nucleus. Neuroreport 2006; 17:1437-41. [PMID: 16932154 DOI: 10.1097/01.wnr.0000227989.15422.71] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
A significant functional role for epidermal growth factor receptor (EGFR) in the suprachiasmatic nucleus is suggested by recent findings that epidermal growth factor receptor and its ligand transforming growth factor-alpha are highly expressed in the suprachiasmatic nucleus. Recent studies indicate that epidermal growth factor receptor activation induces behavioral and physiological effects, strengthening the notion that epidermal growth factor receptor can modulate suprachiasmatic nucleus neural function and behavior. A global transcriptional profiling study is performed to investigate the gene expression response to epidermal growth factor receptor activation in the suprachiasmatic nucleus. The results indicate that all of the observed gene expression response is circadian-time dependent. The response included several genes encoding different neuropeptide receptors, ion channels and kinases. In order to hypothesize the transcription factors underlying the epidermal growth factor receptor response, different circadian-time-dependent gene expression groups were analyzed for enriched transcriptional regulatory elements in the promoters. The results indicate that several transcription factors such as Elk1 and cAMP-responsive element binding protein/activating transcription factor family, known to be 'input points' to the core clock network, are playing a role. Together, these results indicate that epidermal growth factor receptor has a circadian-time-dependent neuromodulatory function in the suprachiasmatic nucleus.
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Affiliation(s)
- Rajanikanth Vadigepalli
- Department of Pathology, Anatomy and Cell Biology, Daniel Baugh Institute for Functional Genomics and Computational Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
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Bany BM, Cross JC. Post-implantation mouse conceptuses produce paracrine signals that regulate the uterine endometrium undergoing decidualization. Dev Biol 2006; 294:445-56. [PMID: 16616120 DOI: 10.1016/j.ydbio.2006.03.006] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2005] [Revised: 02/09/2006] [Accepted: 03/06/2006] [Indexed: 10/24/2022]
Abstract
The uterus undergoes a series of dramatic changes in response to an implanting conceptus that, in some mammalian species, includes differentiation of the endometrial stroma into decidual tissue. This process, called decidualization, can be induced artificially in rodents indicating that the conceptus may not be essential for a proper maternal response in early pregnancy. In order to test this hypothesis, we determined if and how the conceptus affects uterine gene expression. We identified 5 genes (Angpt1, Angpt2, Dtprp, G1p2 and Prlpa) whose steady-state levels in the uterus undergoing decidualization depends on the presence of a conceptus. In situ hybridization revealed region-specific effects which suggested that various components of the conceptus and more than one signal from the conceptus are likely responsible for altering decidual cell function. Using cell culture models we found that trophoblast giant cells secrete a type I interferon-like molecule which can induce G1p2 expression in endometrial stromal cells. Finally, decidual Prlpa expression was reduced in the uterus adjacent to Hand1- and Ets2-deficient embryos, suggesting that normal trophoblast giant cells in the placenta are required for the conceptus-dependent effects on Prlpa expression in the mesometrial decidua. Overall, these results provide support for the hypothesis that molecular signals from the mouse conceptus have local effects on uterine gene expression during decidualization.
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Affiliation(s)
- Brent M Bany
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada.
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18
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Pirttilä TJ, Pitkänen A. Cystatin C expression is increased in the hippocampus following photothrombotic stroke in rat. Neurosci Lett 2006; 395:108-13. [PMID: 16309830 DOI: 10.1016/j.neulet.2005.10.091] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2005] [Revised: 09/16/2005] [Accepted: 10/24/2005] [Indexed: 10/25/2022]
Abstract
Stroke is a major cause of epilepsy, but the molecular mechanisms underlying post-stroke epileptogenesis are unknown. The expression of cystatin C, a cysteine protease inhibitor, is increased in the hippocampus during status epilepticus (SE)-induced epileptogenesis, and regulates both cell death and birth. To test the hypothesis that increased cystatin C expression represents a common molecular alteration induced by epileptogenic brain insults, we investigated the time course, cellular localization, and association of cystatin C expression with neuronal damage during post-stroke epileptogenesis. Stroke was induced with photothrombosis, which leads to epilepsy in approximately 20-30% of rats. Cystatin C expression was increased in the CA1 area of the hippocampus 4 days after photothrombosis, when the diameter of the lesion was the largest. Double-labeling and confocal analysis indicated that cystatin C was expressed in astrocytes and microglia. Unlike after SE, cystatin C expression did not change in the dentate gyrus. Also, increased cystatin C expression was not associated with neurodegeneration, which was demonstrated as an absence of Fluoro Jade B-positive cells in adjacent sections. The present study provides evidence that cystatin C may be involved in cellular alterations that occur after an epileptogenic insult, not only after SE but also after photothrombotic stroke.
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Affiliation(s)
- Terhi J Pirttilä
- A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland
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19
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Gressner AM, Lahme B, Meurer SK, Gressner O, Weiskirchen R. Variable expression of cystatin C in cultured trans-differentiating rat hepatic stellate cells. World J Gastroenterol 2006; 12:731-8. [PMID: 16521186 PMCID: PMC4066123 DOI: 10.3748/wjg.v12.i5.731] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the expression of cystatin C (CysC), its regulation by transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) and the potential interference of CysC with TGF-β1 signaling in this special cell type.
METHODS: We evaluated the CysC expression in cultured, profibrogenic hepatic stellate cells and trans-differentiated myofibroblasts by Northern and Western blotting and confocal laser scanning microscopy.
RESULTS: CysC was increased significantly in the course of trans-differentiation. Both TGF-β1 and PDGF-BB suppressed CysC expression. Furthermore, CysC secretion was induced by the treatment with TGF-β1. Although CysC induced an increased binding affinity of TGF-β receptor type III (beta-glycan) as assessed by chemical cross-linking with [125I]-TGF-β1, it did not modulate TGF-β1 signal transduction as shown by evaluating the Smad2/3 phosphorylation status and [CAGA]-MLP-luciferase reporter gene assay. Interestingly, the shedding of type III TGF-β receptor beta-glycan was reduced in CysC-treated cells. Our data indicated that CysC expression was upregulated during trans-differentiation.
CONCLUSION: Increased CysC levels in the serum of patients suffering from liver diseases are at least partially due to a higher expression in activated hepatic stellate cells. Furthermore, TGF-β1 influences the secretion of CysC, highlighting a potentially important role of cysteine proteases in the progression of hepatic fibrogenesis.
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Affiliation(s)
- Axel M Gressner
- Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University, D-52074 Aachen, Germany.
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Nakanishi T, Ozaki Y, Blomgren K, Tateyama H, Sugiura-Ogasawara M, Suzumori K. Role of cathepsins and cystatins in patients with recurrent miscarriage. Mol Hum Reprod 2005; 11:351-5. [PMID: 15863450 DOI: 10.1093/molehr/gah172] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
In the implantation, trophoblasts penetrate maternal decidua by secreting proteases. It has been reported that cathepsins are highly expressed in the mouse villi, and play an important role in normal embryonal growth and decidualization. In this study, we evaluated cathepsins and their endogenous inhibitors, cystatins, in tissue and serum of patients with recurrent miscarriage. Decidua and villi were surgically collected from 22 patients and 12 healthy women. Immunohistochemistry was performed with antibodies against cathepsins, stefin A (cystatin A), stefin B (cystatin B) and cystatin C. The concentrations of cathepsins, stefins and cystatin C were measured by Enzyme-linked immunosorbent assay. In addition, we measured the serum level of cystatin C in 85 Japanese women with recurrent miscarriage. Staining of cathepsin B, D, H, L, stefin B and cystatin C was observed in the cytoplasm of epithelial cells in decidua. Stefin A was expressed on the surface of the trophoblast. The concentration of cathepsin B and H in patients' decidua was significantly higher than in control individuals. The serum level of cystatin C was significantly lower in patients than in control individuals. Our findings suggest that the regulation of the cathepsin-cystatin system may play an important role in patients with recurrent miscarriage.
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Affiliation(s)
- Tamao Nakanishi
- Department of Obstetrics and Gynecology and 2nd Pathology, Nagoya City University Medical School, 1-Kawasumi, Mizuho-cho, Mizuho, Nagoya, 467-8601, Japan.
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21
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Sokol JP, Schiemann WP. Cystatin C Antagonizes Transforming Growth Factor β Signaling in Normal and Cancer Cells. Mol Cancer Res 2004. [DOI: 10.1158/1541-7786.183.2.3] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Abstract
Cystatin C (CystC) is a secreted cysteine protease inhibitor that regulates bone resorption, neutrophil chemotaxis, and tissue inflammation, as well as resistance to bacterial and viral infections. CystC is ubiquitously expressed and present in most bodily fluids where it inhibits the activities of cathepsins, a family of cysteine proteases that can promote cancer cell invasion and metastasis. Transforming growth factor β (TGF-β) is a multifunctional cytokine endowed with both tumor-suppressing and tumor-promoting activities. We show herein that TGF-β treatment up-regulated CystC transcript and protein in murine 3T3-L1 fibroblasts. Moreover, CystC mRNA expression was down-regulated in ∼50% of human malignancies, particularly cancers of the stomach, uterus, colon, and kidney. Overexpression of CystC in human HT1080 fibrosarcoma cells antagonized their invasion through synthetic basement membranes in part via a cathepsin-dependent pathway. Independent of effects on cathepsin activity, CystC also reduced HT1080 cell gene expression stimulated by TGF-β. Invasion of 3T3-L1 cells occurred through both cathepsin- and TGF-β-dependent pathways. Both pathways were blocked by CystC, but only the TGF-β-dependent pathway was blocked by a CystC mutant (i.e., Δ14CystC) that is impaired in its ability to inhibit cathepsin activity. Moreover, CystC and Δ14CystC both inhibited 3T3-L1 cell gene expression stimulated by TGF-β. We further show that CystC antagonized TGF-β binding to its cell surface receptors, doing so by interacting physically with the TGF-β type II receptor and antagonizing its binding of TGF-β. Collectively, our findings have identified CystC as a novel TGF-β receptor antagonist, as well as a novel CystC-mediated feedback loop that inhibits TGF-β signaling.
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Affiliation(s)
- Jonathan P. Sokol
- Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO
| | - William P. Schiemann
- Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO
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22
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Slayden OD, Hettrich K, Carroll RS, Otto LN, Clark AL, Brenner RM. Estrogen enhances cystatin C expression in the macaque vagina. J Clin Endocrinol Metab 2004; 89:883-91. [PMID: 14764809 DOI: 10.1210/jc.2003-031143] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
Cystatin C is a secreted inhibitor of cysteine proteinases that participates in extracellular matrix remodeling. Whether hormones affect its expression in the vagina was unknown. Consequently, we examined the effects of estradiol (E(2)), progesterone (P), and raloxifene on vaginal cystatin C in rhesus macaques. In experiment 1, ovariectomized animals were treated sequentially with E(2) (14 d) and E(2) + P (14 d) to induce 28-d menstrual cycles. Vaginal samples were collected on d 6, 8, 14, and 28 of the induced cycle. Some cycled animals were deprived of both E(2) + P for 28 d. In experiment 2, ovariectomized animals were treated for 5 months with E(2) alone, E(2) + P, raloxifene, or left untreated. Total RNA from the vaginal wall was analyzed for the cystatin C transcript with a commercially prepared cDNA array and semiquantitative RT-PCR. Vaginal cryosections were analyzed by in situ hybridization for cystatin C transcript and by immunocytochemistry for the protein. E(2) treatment significantly (5-fold; P < 0.05) increased expression of cystatin C transcript over the levels in the hormone-deprived controls, and cotreatment with P (E(2) + P) blocked this effect. Raloxifene treatment did not affect cystatin C expression. In situ hybridization and immunocytochemistry revealed that cystatin C was localized in fibroblasts and smooth muscle cells throughout the vaginal wall but not in smooth muscle cells of arteries or levator ani myocytes. In summary, E(2) increased vaginal cystatin C expression in the fibroblasts and smooth muscle bundles, P suppressed this effect, and raloxifene had no effects on cystatin C. Elevated cystatin C, by suppressing cysteine proteinase activity, may strengthen the vaginal wall and mitigate the potential for pelvic floor prolapse.
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Affiliation(s)
- Ov D Slayden
- Oregon National Primate Research Center, Beaverton, Oregon 97006, USA.
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Vattemi G, Engel WK, McFerrin J, Askanas V. Cystatin C colocalizes with amyloid-beta and coimmunoprecipitates with amyloid-beta precursor protein in sporadic inclusion-body myositis muscles. J Neurochem 2003; 85:1539-46. [PMID: 12787072 DOI: 10.1046/j.1471-4159.2003.01798.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Cystatin C (CC), an endogenous cysteine protease inhibitor, is accumulated within amyloid-beta (A beta) amyloid deposits in Alzheimer's disease (AD) brain and was proposed to play a role in the AD pathogenesis. Because the chemo-morphologic muscle phenotype of sporadic inclusion-body myositis (s-IBM) has several similarities with the phenotype of AD brain, including abnormal accumulation of A beta deposits, we studied expression and localization of CC in muscle biopsies of 10 s-IBM, and 16 disease- and five normal-control muscle biopsies. Physical interaction of CC with amyloid-beta precursor protein (A beta PP) was studied by a combined immunoprecipitation/immunoblotting technique in the s-IBM muscle biopsies and in A beta PP-overexpressing cultured human muscle fibers. In all s-IBM muscle biopsies, CC-immunoreactivity either colocalized with, or was adjacent to, the A beta-immunoreactive inclusions in 80-90% of the vacuolated muscle fibers, mostly in non-vacuolated regions of their cytoplasm. Ultrastructurally, CC immunoreactivity-colocalized with A beta on 6-10 nm amyloid-like fibrils and floccular material. By immunoblotting, CC expression was strongly increased in IBM muscle as compared to the controls. By immunoprecipitation/immunoblotting experiments, CC coimmunoprecipitated with A beta PP, both in s-IBM muscle and in A beta PP-overexpressing cultured normal human muscle fibers. Our studies (i) demonstrate for the first time that CC physically associates with A beta PP, and (ii) suggest that CC may play a novel role in the s-IBM pathogenesis, possibly by influencing A beta PP processing and A beta deposition.
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Affiliation(s)
- Gaetano Vattemi
- USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, California 90017-1912, USA
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24
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Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, An P, Antonarakis SE, Attwood J, Baertsch R, Bailey J, Barlow K, Beck S, Berry E, Birren B, Bloom T, Bork P, Botcherby M, Bray N, Brent MR, Brown DG, Brown SD, Bult C, Burton J, Butler J, Campbell RD, Carninci P, Cawley S, Chiaromonte F, Chinwalla AT, Church DM, Clamp M, Clee C, Collins FS, Cook LL, Copley RR, Coulson A, Couronne O, Cuff J, Curwen V, Cutts T, Daly M, David R, Davies J, Delehaunty KD, Deri J, Dermitzakis ET, Dewey C, Dickens NJ, Diekhans M, Dodge S, Dubchak I, Dunn DM, Eddy SR, Elnitski L, Emes RD, Eswara P, Eyras E, Felsenfeld A, Fewell GA, Flicek P, Foley K, Frankel WN, Fulton LA, Fulton RS, Furey TS, Gage D, Gibbs RA, Glusman G, Gnerre S, Goldman N, Goodstadt L, Grafham D, Graves TA, Green ED, Gregory S, Guigó R, Guyer M, Hardison RC, Haussler D, Hayashizaki Y, Hillier LW, Hinrichs A, Hlavina W, Holzer T, Hsu F, Hua A, Hubbard T, Hunt A, Jackson I, Jaffe DB, Johnson LS, Jones M, Jones TA, Joy A, Kamal M, Karlsson EK, et alWaterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, An P, Antonarakis SE, Attwood J, Baertsch R, Bailey J, Barlow K, Beck S, Berry E, Birren B, Bloom T, Bork P, Botcherby M, Bray N, Brent MR, Brown DG, Brown SD, Bult C, Burton J, Butler J, Campbell RD, Carninci P, Cawley S, Chiaromonte F, Chinwalla AT, Church DM, Clamp M, Clee C, Collins FS, Cook LL, Copley RR, Coulson A, Couronne O, Cuff J, Curwen V, Cutts T, Daly M, David R, Davies J, Delehaunty KD, Deri J, Dermitzakis ET, Dewey C, Dickens NJ, Diekhans M, Dodge S, Dubchak I, Dunn DM, Eddy SR, Elnitski L, Emes RD, Eswara P, Eyras E, Felsenfeld A, Fewell GA, Flicek P, Foley K, Frankel WN, Fulton LA, Fulton RS, Furey TS, Gage D, Gibbs RA, Glusman G, Gnerre S, Goldman N, Goodstadt L, Grafham D, Graves TA, Green ED, Gregory S, Guigó R, Guyer M, Hardison RC, Haussler D, Hayashizaki Y, Hillier LW, Hinrichs A, Hlavina W, Holzer T, Hsu F, Hua A, Hubbard T, Hunt A, Jackson I, Jaffe DB, Johnson LS, Jones M, Jones TA, Joy A, Kamal M, Karlsson EK, Karolchik D, Kasprzyk A, Kawai J, Keibler E, Kells C, Kent WJ, Kirby A, Kolbe DL, Korf I, Kucherlapati RS, Kulbokas EJ, Kulp D, Landers T, Leger JP, Leonard S, Letunic I, Levine R, Li J, Li M, Lloyd C, Lucas S, Ma B, Maglott DR, Mardis ER, Matthews L, Mauceli E, Mayer JH, McCarthy M, McCombie WR, McLaren S, McLay K, McPherson JD, Meldrim J, Meredith B, Mesirov JP, Miller W, Miner TL, Mongin E, Montgomery KT, Morgan M, Mott R, Mullikin JC, Muzny DM, Nash WE, Nelson JO, Nhan MN, Nicol R, Ning Z, Nusbaum C, O'Connor MJ, Okazaki Y, Oliver K, Overton-Larty E, Pachter L, Parra G, Pepin KH, Peterson J, Pevzner P, Plumb R, Pohl CS, Poliakov A, Ponce TC, Ponting CP, Potter S, Quail M, Reymond A, Roe BA, Roskin KM, Rubin EM, Rust AG, Santos R, Sapojnikov V, Schultz B, Schultz J, Schwartz MS, Schwartz S, Scott C, Seaman S, Searle S, Sharpe T, Sheridan A, Shownkeen R, Sims S, Singer JB, Slater G, Smit A, Smith DR, Spencer B, Stabenau A, Stange-Thomann N, Sugnet C, Suyama M, Tesler G, Thompson J, Torrents D, Trevaskis E, Tromp J, Ucla C, Ureta-Vidal A, Vinson JP, Von Niederhausern AC, Wade CM, Wall M, Weber RJ, Weiss RB, Wendl MC, West AP, Wetterstrand K, Wheeler R, Whelan S, Wierzbowski J, Willey D, Williams S, Wilson RK, Winter E, Worley KC, Wyman D, Yang S, Yang SP, Zdobnov EM, Zody MC, Lander ES. Initial sequencing and comparative analysis of the mouse genome. Nature 2002; 420:520-62. [PMID: 12466850 DOI: 10.1038/nature01262] [Show More Authors] [Citation(s) in RCA: 4938] [Impact Index Per Article: 214.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2002] [Accepted: 10/31/2002] [Indexed: 12/18/2022]
Abstract
The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.
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MESH Headings
- Animals
- Base Composition
- Chromosomes, Mammalian/genetics
- Conserved Sequence/genetics
- CpG Islands/genetics
- Evolution, Molecular
- Gene Expression Regulation
- Genes/genetics
- Genetic Variation/genetics
- Genome
- Genome, Human
- Genomics
- Humans
- Mice/classification
- Mice/genetics
- Mice, Knockout
- Mice, Transgenic
- Models, Animal
- Multigene Family/genetics
- Mutagenesis
- Neoplasms/genetics
- Physical Chromosome Mapping
- Proteome/genetics
- Pseudogenes/genetics
- Quantitative Trait Loci/genetics
- RNA, Untranslated/genetics
- Repetitive Sequences, Nucleic Acid/genetics
- Selection, Genetic
- Sequence Analysis, DNA
- Sex Chromosomes/genetics
- Species Specificity
- Synteny
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