Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a key regulator of lipid and glucose metabolism and is implicated in inflammation. We investigated the effects of the PPAR-alpha activator fenofibrate on, as well as the role of redox-regulated transcription factors, in the development of left ventricular (LV) hypertrophy and heart failure in Dahl salt-sensitive (DS) rats. DS rats were fed a high-salt diet and treated with either fenofibrate (30 or 50 mg/kg per day) or vehicle from 7 weeks of age. Fenofibrate inhibited the development of compensated hypertensive LV hypertrophy, attenuated the LV relaxation abnormality and systolic dysfunction, and improved the survival rate in DS rats. It also prevented a decrease in the ratio of reduced to oxidized glutathione and inhibited up-regulation of the DNA binding activities of the redox-regulated transcription factors NF-kappaB, AP-1, Egr-1, SP1, and Ets-1 induced in the left ventricle by the high-salt diet. Expression of target genes for these transcription factors, including those for adhesion molecules (VCAM-1, ICAM-1), cytokines (MCP-1), growth factors (TGF-beta, PDGF-B), and osteopontin, was also increased by the high-salt diet in a manner sensitive to treatment with fenofibrate. Furthermore, the infiltration of macrophages and T lymphocytes into the left ventricle and the increase in the plasma concentration of C-reactive protein were inhibited by fenofibrate. The PPAR-alpha activator fenofibrate thus attenuated the progression of heart failure and improved the survival rate in this rat model. These effects were associated with inhibition of the inflammatory response and of activation of redox-regulated transcription factors in the left ventricle.
J Mol Cell Cardiol 2006 Aug
PMID:Attenuation of cardiac dysfunction by a PPAR-alpha agonist is associated with down-regulation of redox-regulated transcription factors. 1680 63

Osteopontin is a multifunctional protein secreted by epithelial cells of various tissues. Its expression in the adult rat major salivary glands has not yet been studied. We examined osteopontin expression by immunohistochemistry using a well characterized monoclonal antibody. Submandibular glands of young adult male rats (70-100 days old) showed specific expression in secretion granules of granular duct cells but also in cells of the striated ducts and excretory duct. In the major sublingual as well as the parotid gland expression was found solely in the duct system. In addition, a few interstitial-like cells exhibiting very strong immunostaining for osteopontin could be found in either organ. Expression could neither be seen in acinar cells nor in cells of the intercalated ducts. Moreover, in submandibular glands of more aged rats (6- to 7-month old) which show well developed granular convoluted tubules, there was almost exclusive expression of osteopontin in granular duct cells as well as in some interstitial-like cells, but barely in the striated/excretory duct system. Western blot analysis of the submandibular gland showed a specific band migrating at approximately 74 kDa, detectable at both age stages. Osteopontin secreted fom granular duct cells may influence the composition of the saliva, e.g. thereby modulating pathways affecting sialolithiasis. Its expression in striated duct cells may also hint to roles such as cell-cell attachment or cell differentiation. The cell-specific expression detected in the rat major salivary glands differs in part from that reported in mice, human and monkey.
J Mol Histol 2006 Jan
PMID:Distinct immunohistochemical expression of osteopontin in the adult rat major salivary glands. 1681 53

Vascular calcification (VC) is an orchestrated event, evoking the programmed process of the osteogenesis and triggered by inflammatory cytokines active at vascular level. VC is a dynamic process in which the vessel wall intima, media and also cardiac valves may be involved. Intimal calcification is an endochondral ossification process in which type II collagen is mineralized by calcium deposition. In contrast, an intra-membranous ossification process leads to medial calcification, while a dystrophic calcification process is responsible for valvular calcification. Mechanisms involved in VC may be summarized as: 1. Activation of osteogenesis in the vessel wall, 2. Loss of inhibitory factors, 3. Enhanced bone turnover, and 4. Abnormalities in mineral metabolism. The signaling axis constituted by osteoprotegerin (OPG), receptor activator nuclear factor kB (RANK) and its ligand (RANKL), along with the monocyte colony stimulating factor (M-CSF) and the transcription factor core Binding protein (Cbfa-1), play a pivotal role in the control of VC. In contrast, fetuin-A, matrix G1a protein (MGP) and osteopontin (OPN) control the inhibition of VC. In addition, abnormal mineral metabolism with enhanced phosphates availability favors calcium deposition. The inflammatory cytokines interleukin (IL-1) and tumor necrosis factor (TNF)-alpha enhance OPG and RANKL function in the vessel wall leading to VC. VC is a controlled process, depending on the balance between osteoblastic and osteoclastic influences and further modulated by the influence of risk factors like diabetes, smoking, age, hypertension and dyslipidemia. Recent advances in diagnostic tools such as with multi-detector computed tomography (MDCT) and electron beam computed tomography (EBCT), may help diagnosis and delineation of VC in the clinical setting and aid in understanding its prognostic value.
Curr Mol Med 2006 Aug
PMID:Molecular determinants of vascular calcification: a bench to bedside view. 1691 72

We previously reported that accessory sex gland fluid (AGF) from high fertility (HF) bulls influenced the oocyte-penetrating capacity of cauda epididymal sperm from low fertility (LF) bulls, based on in vitro fertilization (IVF) assays. The present study determined if AGF proteins were associated with these effects. Nineteen IVF assays with 12 bulls were grouped as follows. Group I (n = 8): assays where sperm from LF bulls exposed to AGF from HF bulls had greater oocyte penetration than exposed to homologous AGF. Group II (n = 7): sperm from LF bulls to AGF from HF bulls versus homologous AGF showed no significant differences. Group III (n = 4): sperm from LF bulls treated with homologous AGF had greater fertility than sperm treated with AGF from HF bulls. Sire fertility was based on nonreturn rates (NNR) and AGF collected by artificial vagina from bulls with cannulated vasa deferentia. Two-dimensional SDS-PAGE maps of AGF were analyzed by PDQuest and proteins identified by tandem mass spectrometry and Western blots. Differences in spot intensity between AGF of HF and LF bulls were compared across groups of IVF assays (P < 0.05). The expression of BSP A1/A2 and A3, BSP 30 kDa, clusterin, albumin, phospholipase A(2) (PLA(2)), and osteopontin was greater in the AGF of HF bulls in Group I as compared to Groups II and III. Conversely, there was less nucleobindin in the AGF of HF bulls in Group I than in Groups II and III. This is the first report of nucleobindin (58 kDa/pI 5.6) in male reproductive fluids, using both immunoblots and mass spectrometry. Thus, the effect of AGF from HF bulls on epididymal sperm is likely the result of specific proteins expressed in the AGF.
Mol Reprod Dev 2007 Feb
PMID:Proteins of the accessory sex glands associated with the oocyte-penetrating capacity of cauda epididymal sperm from holstein bulls of documented fertility. 1694 73

Targeted disruption of the epididymis-specific HE6/Gpr64 receptor gene in mice led to male infertility. In order to characterize the phenotype at a molecular level, we compared the gene expression patterns of wild type (wt) versus knockout (KO) caput epididymides. The caput region of KO males, although morphologically normal, nevertheless showed an aberrant expression pattern. Combining micro array analysis, differential library screening, Northern blot analysis and quantitative RT-PCR, we found that the knockout of the HE6/Gpr64 receptor was mainly associated with the downregulation of genes specific to the initial segment. The list of KO downregulated transcripts comprised Enpp2/autotaxin, the lipocalins 8 and 9, the beta-defensin Defb42, cystatins 8 and 12, as well as the membrane proteins Adam (A Disintegrin And Metalloprotease) 28, claudin-10, EAAC1, and the novel Me9. Clusterin/ApoJ and osteopontin/Spp1 mRNAs, on the other hand, were upregulated in the KO tissues. The Me9 transcript was studied in further detail, and we report here a cluster of related epididymis-specific genes. Me9 is specifically expressed in the initial segment and is representative of a novel and highly conserved mammalian gene family. The family consists of single-exon genes only; intron-containing paralogs have not yet been ascertained. The cloned cDNA sequences predicted hydrophobic polytopic membrane proteins containing the DUF716 motif. Protein expression was shown in the rodent caput epididymidis but remained uncertain in primates.
Mol Reprod Dev 2007 May
PMID:Novel epididymis-specific mRNAs downregulated by HE6/Gpr64 receptor gene disruption. 1703 53

Secreted proteins, which may be involved in the regulation of various biological processes, are the potential targets for diagnosis and treatment of diverse diseases. In this study, to identify the human hepatoma HepG2 cells-derived secreted proteins more extensively, we applied the protein sample preparations using the combinations of denaturation methods and molecular-mass cutoff via ultrafiltration to the two-dimensional liquid chromatography coupled with tandem mass spectrometry (2D LC-MS/MS) analysis. We were able to identify a total of 86 proteins containing widely known secreted proteins of HepG2 such as alpha-fetoprotein, of which 73 proteins including 27 signal peptide-containing proteins have never been reported to be secreted from HepG2 cells in other proteomic studies. Among the identified signal peptide-containing proteins, ten proteins such as growth differentiation factor 15, osteopontin and stanniocalcin 2 were discovered as new secreted proteins of HepG2 cells. These observations suggest that the combinations of different sample preparation methods and 2D LC-MS/MS analysis are useful for identifying a wider range of low-abundance proteins and that the secreted proteins from HepG2 identified in this study may be useful as liver-specific biomarkers for diagnosis and treatment.
Mol Cell Biochem 2007 Apr
PMID:Extracellular proteome of human hepatoma cell, HepG2 analyzed using two-dimensional liquid chromatography coupled with tandem mass spectrometry. 1710 77

A matricellular protein, osteopontin (OPN), is expressed in response to mechanical stress and similar stimuli in the heart, integrates the inter-ECM signal transduction network of component cells, and maintains efficient contractility through quantitative and qualitative control of extracellular matrix (ECM) proteins. In particular, OPN is re-expressed in the process of tissue damage; combines with other cell growth factors, cytokines, chemokines, and proteases as a cytokine itself or as an adhesion molecule; and controls the differentiation and growth of cells involved in restoration of tissues by controlling inter-cellular signal transduction and production of ECM proteins through regulation of expression levels and activity. A study using mice lacking a functional OPN gene indicated that tissue restoration fails and collagen deposition is inhibited through matrix metalloproteinases (MMPs) in mice lacking OPN. Thus, while OPN accelerates the cardiovascular remodeling process, it also regulates the balance of various inter-cellular activities. In addition, OPN not only promotes arteriosclerosis but is also closely associated with angiogenesis. With the roles of OPN expected to be clinically elucidated, the clinical use of OPN for control of cardiovascular remodeling may be feasible. Points (1) Osteopontin (OPN) efficiently propagates contraction in the heart as a matricellular protein and thereby controls ECM proteins both quantitatively and qualitatively. (2) The quantitative and qualitative control of ECM proteins is involved in interaction with OPN receptors including those of the integrin family, CD44, and others. (3) OPN promotes myocardial remodeling through TGFbeta and MMPs. (4) OPN not only promotes arteriosclerosis but is also closely associated with arteriosteogenesis. (5) In animals lacking OPN, tissue remodeling process is inhibited, especially in terms of fibrosis after myocardial infarction. (6) While the significance of OPN as an immune system molecule is still unclear in detail, the significance of OPN in the regenerative immune system has begun to be determined.
Mol Cell Biochem 2007 Jun
PMID:Osteopontin and cardiovascular system. 1713 80

Osteopontin (OPN) is a chemokine like phosphorylated glycoprotein that plays important role in cancer progression. Extensive research from various laboratories has demonstrated the likely role of OPN in regulating the cell signaling that ultimately controls tumor growth and metastasis. Several earlier reports indicated that OPN is associated with various cancers; but its functional role in carcinogenesis is still not well defined. Besides the role of OPN in tumor biology, several studies have demonstrated the pathophysiological role of OPN in diverse biological events. This review will focus on recent advances in understanding the molecular mechanism by which OPN regulates a series of signaling cascades through activation of various kinases and transcription factors that ultimately control the expression of downstream effector genes, which contribute to tumor progression and angiogenesis in vitro and animal models. We will also provide evidences that suggest the enhanced expression of OPN is not only associated with several tumor types, but its level of expression is directly correlated to various stages of the clinical specimens of breast and prostate cancers. These studies may be useful for identifying novel OPN-based therapeutic approach for the treatment of cancer.
Curr Mol Med 2006 Dec
PMID:The multifaceted roles of osteopontin in cell signaling, tumor progression and angiogenesis. 1716 34

Elucidation of protease substrate degradomes is essential for understanding the function of proteolytic pathways in the protease web and how proteases regulate cell function. We identified matrix metalloproteinase-2 (MMP-2) cleaved proteins, solubilized pericellular matrix, and shed cellular ectodomains in the cellular context using a new multiplex proteomics approach. Tryptic peptides of intact and cleaved proteins, collected from conditioned culture medium of Mmp2(-/-) fibroblasts expressing low levels of transfected active human MMP-2 at different time points, were amine-labeled with iTRAQ mass tags. Peptide identification and relative quantitation between active and inactive protease transfectants were achieved following tag fragmentation during tandem MS. Known substrates of MMP-2 were identified thereby validating this technique with many novel MMP-2 substrates including the CX(3)CL1 chemokine fractalkine, osteopontin, galectin-1, and HSP90alpha also being identified and biochemically confirmed. In comparison with ICAT-labeling and quantitation, 8-9-fold more proteins and substrates were identified by iTRAQ. "Peptide mapping," the location of multiple peptides identified within a particular protein by iTRAQ in combination with their relative abundance ratios, enabled the domain shed and general location of the cleavage site to be identified in the native cellular substrate. Hence this advance in degradomics cell-based screens for native protein substrates casts new light on the roles for proteases in cell function.
Mol Cell Proteomics 2007 Apr
PMID:Proteomics discovery of metalloproteinase substrates in the cellular context by iTRAQ labeling reveals a diverse MMP-2 substrate degradome. 1720 Jan 5

Adipose-derived stem cells (ASCs) are considered to be multipotent mesenchymal stem cells that are easily induced to differentiate into functional osteoblasts both in vitro and in vivo. Osterix (Osx) is a zinc finger-containing transcription factor of Sp gene family, which plays important roles in bone development and mineralization. In this study, we hypothesized that overexpression of Osx in murine ASCs would promote their osteogenic differentiation in vitro. A plasmid expressing Osx (pcDNA3.1-Osx) was constructed and applied to transfect monolayers of murine ASCs. Then expression of bone-related genes, nodule formation, proliferation rate, and alkaline phosphatase activity were examined to evaluate the osteogenic potential of ASCs with pcDNA3.1-Osx transfection. Results of RT-PCR and immunohistochemistry showed that pcDNA3.1-Osx transfection enhanced the expression of bone matrix proteins, such as bone sialoprotein, osteocalcin, osteopontin, and Collagen type I in ASCs. At the same time, overexpression of Osx in ASCs enhanced alkaline phosphatase activity and capability to form mineralized nodules, while not inhibited their proliferation rate. These results indicated that pcDNA3.1-Osx transfection promoted the osteogenic differentiation of ASCs, while not affecting their proliferative ability. Since they can be easily isolated and genetically modified, ASCs are hopeful cell sources in the further application of hard tissue engineering.
Mol Cell Biochem 2007 Jul
PMID:Osteogenic differentiation of adipose derived stem cells promoted by overexpression of osterix. 1720 79


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