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Article ; Online: Pudgy mouse rib deformities emanate from abnormal paravertebral longitudinal cartilage/bone accumulations.

Shapiro, Frederic / Wang, Jamie / Flynn, Evelyn / Wu, Joy Y

2024 Volume 13, Issue 1

Abstract: The pudgy (pu/pu) mouse, caused by a recessive mutation in the Notch family Delta like-3 gene (Dll3), has severe rib, vertebral body and intervertebral disc abnormalities. Using whole-mount preparations and serial histologic sections we demonstrate: 1) ... ...

Abstract	The pudgy (pu/pu) mouse, caused by a recessive mutation in the Notch family Delta like-3 gene (Dll3), has severe rib, vertebral body and intervertebral disc abnormalities. Using whole-mount preparations and serial histologic sections we demonstrate: 1) localized paravertebral longitudinal cartilage/bone accumulations (PVLC/BAs) invariably associated with branched, fused and asymmetrically spaced ribs that emanate from it laterally; 2) abnormal rib formation immediately adjacent to abnormal vertebral body and intervertebral disc formation in asymmetric right/left fashion; and 3) patterns of rib deformation that differ in each mouse. Normal BALB/c embryo and age-matched non-affected pu/+ mice assessments allow for pu/pu comparisons. The Dll3 Notch family gene is involved in normal somitogenesis via the segmentation clock mechanism. Although pathogenesis of rib deformation is initially triggered by the Dll3 gene mutation, these findings of abnormal asymmetric costo-vertebral region structure imply that differing patterns cannot be attributed to this single gene mutation alone. All findings implicate a dual mechanism of malformation: the Dll3 gene mutation leading to subtle timing differences in traveling oscillation waves of the segmentation clock and further subsequent misdirection of tissue formation by altered chemical reaction-diffusion and epigenetic landscape responses. PVLC/BAs appear as primary supramolecular structures underlying severe rib malformation associated both with time-sensitive segmentation clock mutations and subsequent reactions.
MeSH term(s)	Animals ; Mice ; Cartilage ; Embryo, Mammalian ; Epigenomics ; Mutation ; Receptors, Notch ; Ribs/abnormalities ; Intracellular Signaling Peptides and Proteins/genetics ; Membrane Proteins/genetics
Chemical Substances	Receptors, Notch ; Dll3 protein, mouse ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins
Language	English
Publishing date	2024-01-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2632264-X
ISSN	2046-6390 ; 2046-6390
ISSN (online)	2046-6390
ISSN	2046-6390
DOI	10.1242/bio.060139
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Article: Structural differences in epiphyseal and physeal hypertrophic chondrocytes.

Shapiro, Frederic / Flynn, Evelyn

BoneKEy reports

2015 Volume 4, Page(s) 663

Abstract: We have observed that epiphyseal and physeal hypertrophic chondrocytes in BALB/c mice show considerable differences of light microscopic and ultrastructural appearance, even when the cells are at the same stage of differentiation. In addition, cell ... ...

Abstract	We have observed that epiphyseal and physeal hypertrophic chondrocytes in BALB/c mice show considerable differences of light microscopic and ultrastructural appearance, even when the cells are at the same stage of differentiation. In addition, cell structure maintenance improved with tissue preparation controlled for osmolarity and for membrane stabilization using 0.5% ruthenium hexammine trichloride (RHT) for both light microscopy (LM) and electron microscopy (EM) or 0.5% lanthanum nitrate for LM. Physeal hypertrophic chondrocytes showed a gradual increase in size closer to the metaphysis and a change in shape as cells elongated along the long axis. The nucleus remained central, with uniformly dispersed chromatin, and the rough endoplasmic reticulum (RER) was randomly dispersed throughout cytoplasm with little to no presence against the cell membrane. Even the lowermost cells showed thin elongated or dilated cisternae of RER and intact cell membranes. Epiphyseal chondrocytes remained circular to oval with no elongation. Nucleus and RER were positioned as a complete transcellular central nucleocytoplasmic column or as an incomplete bud with RER of the column/bud always continuous with RER peripherally against the intact cell membrane. RER was densely packed with parallel cisternae with adjacent cytoplasm empty of organelles but often filled with circular deposits of moderately electron-dense material consistent with fat. Optimal technique for LM involved fixation using glutaraldehyde (GA) 1.3%, paraformaldehyde (PFA) 1% and RHT 0.5% (mOsm 606) embedded in JB-4 plastic and stained with 0.5% toluidine blue. Optimal technique for EM used fixation with GA 1.3%, PFA 1%, RHT 0.5% and cacodylate buffer 0.03 M (mOsm 511) and post-fixation including 1% osmium tetroxide. These observations lead to the possibility that the same basic cell, the hypertrophic chondrocyte, has differing functional mechanisms at different regions of the developing bone.
Language	English
Publishing date	2015-04-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2816308-4
ISSN	2047-6396
ISSN	2047-6396
DOI	10.1038/bonekey.2015.30
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Article ; Online: A Combination therapy using an mTOR inhibitor and Honokiol effectively induces autophagy through the modulation of AXL and Rubicon in renal cancer cells and restricts renal tumor growth following organ transplantation.

Sabarwal, Akash / Wedel, Johannes / Liu, Kaifeng / Zurakowski, David / Chakraborty, Samik / Flynn, Evelyn / Briscoe, David M / Balan, Murugabaskar / Pal, Soumitro

Carcinogenesis

2021 Volume 43, Issue 4, Page(s) 360–370

Abstract: Development of cancer, including renal cancer, is a major problem in immunosuppressed patients. The mTOR inhibitor Rapamycin (RAPA) is used as an immunosuppressive agent in patients with organ transplants and other immunological disorders; and it also ... ...

Abstract	Development of cancer, including renal cancer, is a major problem in immunosuppressed patients. The mTOR inhibitor Rapamycin (RAPA) is used as an immunosuppressive agent in patients with organ transplants and other immunological disorders; and it also has antitumorigenic potential. However, long-term use of RAPA causes reactivation of Akt, and ultimately leads to enhanced tumor growth. Honokiol (HNK) is a natural compound, which possesses both anti-inflammatory and antitumorigenic properties. In this study, we investigated the effect of a novel combination therapy using RAPA + HNK on allograft survival and post-transplantation renal tumor growth. We observed that it effectively modulated the expression of some key regulatory molecules (like Carabin, an endogenous Ras inhibitor; and Rubicon, a negative regulator of autophagy) that play important roles in tumor cell growth and survival. This combination induced toxic autophagy and apoptosis to promote cancer cell death; and was associated with a reduced expression of the tumor-promoting receptor tyrosine kinase AXL. Finally, we utilized a novel murine model to examine the effect of RAPA + HNK on post-transplantation renal tumor growth. The combination treatment prolonged the allograft survival and significantly inhibited post-transplantation tumor growth. It was associated with reduced tumor expression of Rubicon and the cytoprotective/antioxidant heme oxygenase-1 to overcome therapeutic resistance. It also downregulated the coinhibitory programmed death-1 ligand, which plays major role(s) in the immune escape of tumor cells. Together, this combination treatment has a great potential to restrict renal tumor growth in transplant recipients as well as other immunosuppressed patients.
MeSH term(s)	Animals ; Apoptosis ; Autophagy ; Biphenyl Compounds ; Cell Line, Tumor ; Humans ; Intracellular Signaling Peptides and Proteins ; Kidney Neoplasms/pathology ; Lignans ; Mice ; Organ Transplantation ; Sirolimus/pharmacology ; Sirolimus/therapeutic use ; TOR Serine-Threonine Kinases
Chemical Substances	Biphenyl Compounds ; Intracellular Signaling Peptides and Proteins ; Lignans ; Rubcn protein, mouse ; honokiol (11513CCO0N) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2021-12-26
Publishing country	England
Document type	Journal Article
ZDB-ID	603134-1
ISSN	1460-2180 ; 0143-3334
ISSN (online)	1460-2180
ISSN	0143-3334
DOI	10.1093/carcin/bgab126
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Article: Activation of c-Met in cancer cells mediates growth-promoting signals against oxidative stress through Nrf2-HO-1.

Chakraborty, Samik / Balan, Murugabaskar / Flynn, Evelyn / Zurakowski, David / Choueiri, Toni K / Pal, Soumitro

Oncogenesis

2019 Volume 8, Issue 2, Page(s) 7

Abstract: Any imbalance between reactive oxygen species (ROS) generation and the anti-oxidant capacity lead to cellular oxidative stress. Many chemotherapeutic agents mediate their cytotoxic functions through the generation of ROS. c-Met, a receptor tyrosine ... ...

Abstract	Any imbalance between reactive oxygen species (ROS) generation and the anti-oxidant capacity lead to cellular oxidative stress. Many chemotherapeutic agents mediate their cytotoxic functions through the generation of ROS. c-Met, a receptor tyrosine kinase, is over-expressed in renal cancer and plays very crucial role(s) in its growth and survival. Here, we show that c-Met activation protected renal cancer cells from ROS, oxidative stress and cytotoxicity induced by the anti-cancer agent sorafenib (used for renal cancer treatment); and it markedly attenuated sorafenib-induced DNA damage. Activated c-Met promoted the anti-apoptotic proteins (Bcl-2 and Bcl-xL) and inhibited apoptotic cleaved caspase-3. We found that the cytoprotective function of c-Met against sorafenib-induced ROS generation and apoptosis was mediated primarily through the activation of anti-oxidant Nrf2-HO-1. c-Met promoted the nuclear localization of Nrf2 and hindered its binding with the inhibitory protein Keap1. Silencing of Nrf2 attenuated the protective action of c-Met against sorafenib-induced oxidative stress. To evaluate the physiological significance of our findings, in a tumor xenograft model, we observed that a combination treatment with pharmacological inhibitors of c-Met and it's anti-oxidant downstream effecter HO-1 markedly reduced the growth of renal tumor in vivo; it increased the oxidative stress, DNA damage and apoptotic markers in the tumor xenografts, along with reduced tumor vessel density. Our observations indicate that the c-Met-Nrf2-HO-1 pathway plays a vital role in relieving ROS-mediated oxidative stress of renal tumors. Targeting this pathway can significantly increase the oxidative stress to promote apoptotic death of cancer cells.
Language	English
Publishing date	2019-01-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2674437-5
ISSN	2157-9024
ISSN	2157-9024
DOI	10.1038/s41389-018-0116-9
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Article ; Online: Honokiol inhibits c-Met-HO-1 tumor-promoting pathway and its cross-talk with calcineurin inhibitor-mediated renal cancer growth.

Balan, Murugabaskar / Chakraborty, Samik / Flynn, Evelyn / Zurakowski, David / Pal, Soumitro

Scientific reports

2017 Volume 7, Issue 1, Page(s) 5900

Abstract: Honokiol (HNK) is a small molecule with potent anti-inflammatory and anti-tumorigenic properties; yet the molecular targets of HNK are not well studied. Hyperactivation of the receptor tyrosine kinase c-Met and overexpression of the cytoprotective enzyme ...

Abstract	Honokiol (HNK) is a small molecule with potent anti-inflammatory and anti-tumorigenic properties; yet the molecular targets of HNK are not well studied. Hyperactivation of the receptor tyrosine kinase c-Met and overexpression of the cytoprotective enzyme heme oxygenase-1 (HO-1) play a critical role in the growth and progression of renal cell carcinoma (RCC). Interestingly, the calcineurin inhibitor (CNI) cyclosporine A (CsA), an immunosuppressant used to prevent allograft rejection, can also increase the risk of RCC in transplant patients. We studied the potential role of c-Met signaling axis on CNI-induced renal tumor growth and tested the anti-tumor efficacy of HNK. Importantly, CNI treatment promoted c-Met induction and enhanced c-Met-induced Ras activation. We found that HNK treatment effectively down-regulated both c-Met phosphorylation and Ras activation in renal cancer cells. It inhibited the expression of both c-Met- and CNI-induced HO-1, and promoted cancer cell apoptosis. In vivo, HNK markedly inhibited CNI-induced renal tumor growth; and it decreased the expression of phospho-c-Met and HO-1 and reduced blood vessel density in tumor tissues. Our results suggest a novel mechanism(s) by which HNK exerts its anti-tumor activity through the inhibition of c-Met-Ras-HO-1 axis; and it can have significant therapeutic potential to prevent post-transplantation cancer in immunosuppressed patients.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Biphenyl Compounds/pharmacology ; Biphenyl Compounds/therapeutic use ; Calcineurin Inhibitors/pharmacology ; Calcineurin Inhibitors/therapeutic use ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Down-Regulation/drug effects ; Heme Oxygenase-1/metabolism ; Hepatocyte Growth Factor/pharmacology ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Kidney Neoplasms/blood supply ; Kidney Neoplasms/metabolism ; Kidney Neoplasms/pathology ; Lignans/pharmacology ; Lignans/therapeutic use ; Mice, Nude ; Neovascularization, Pathologic/drug therapy ; Neovascularization, Pathologic/pathology ; Neovascularization, Physiologic/drug effects ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-met/metabolism ; ras Proteins/metabolism
Chemical Substances	Biphenyl Compounds ; Calcineurin Inhibitors ; Lignans ; honokiol (11513CCO0N) ; Hepatocyte Growth Factor (67256-21-7) ; Heme Oxygenase-1 (EC 1.14.14.18) ; MET protein, human (EC 2.7.10.1) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2017-07-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-05455-1
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Article: Histopathology of osteogenesis imperfecta bone. Supramolecular assessment of cells and matrices in the context of woven and lamellar bone formation using light, polarization and ultrastructural microscopy.

Shapiro, Frederic / Maguire, Kathleen / Swami, Srilatha / Zhu, Hui / Flynn, Evelyn / Wang, Jamie / Wu, Joy Y

Bone reports

2020 Volume 14, Page(s) 100734

Abstract: Diaphyseal long bone cortical tissue from 30 patients with lethal perinatal Sillence II and progressively deforming Sillence III osteogenesis imperfecta (OI) has been studied at multiple levels of structural resolution. Interpretation in the context of ... ...

Abstract	Diaphyseal long bone cortical tissue from 30 patients with lethal perinatal Sillence II and progressively deforming Sillence III osteogenesis imperfecta (OI) has been studied at multiple levels of structural resolution. Interpretation in the context of woven to lamellar bone formation by mesenchymal osteoblasts (MOBLs) and surface osteoblasts (SOBLs) respectively demonstrates lamellar on woven bone synthesis as an obligate self-assembly mechanism and bone synthesis following the normal developmental pattern but showing variable delay in maturation caused by structurally abnormal or insufficient amounts of collagen matrix. The more severe the variant of OI is, the greater the persistence of woven bone and the more immature the structural pattern; the pattern shifts to a structurally stronger lamellar arrangement once a threshold accumulation for an adequate scaffold of woven bone has been reached. Woven bone alone characterizes lethal perinatal variants; variable amounts of woven and lamellar bone occur in progressively deforming variants; and lamellar bone increasingly forms rudimentary and then partially compacted osteons not reaching full compaction. At differing levels of microscopic resolution: lamellar bone is characterized by short, obliquely oriented lamellae with a mosaic appearance in progressively deforming forms; polarization defines tissue conformations and localizes initiation of lamellar formation; ultrastructure of bone forming cells shows markedly dilated rough endoplasmic reticulum (RER) and prominent Golgi bodies with disorganized cisternae and swollen dispersed tubules and vesicles, structural indications of storage disorder/stress responses and mitochondrial swelling in cells with massively dilated RER indicating apoptosis; ultrastructural matrix assessments in woven bone show randomly oriented individual fibrils but also short pericellular bundles of parallel oriented fibrils positioned obliquely and oriented randomly to one another and in lamellar bone show unidirectional fibrils that deviate at slight angles to adjacent bundles and obliquely oriented fibril groups consistent with twisted plywood fibril organization. Histomorphometric indices, designed specifically to document woven and lamellar conformations in normal and OI bone, establish ratios for: i)
Language	English
Publishing date	2020-12-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2821774-3
ISSN	2352-1872
ISSN	2352-1872
DOI	10.1016/j.bonr.2020.100734
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Article ; Online: The cn/cn dwarf mouse. Histomorphometric, ultrastructural, and radiographic study in mutants corresponding to human acromesomelic dysplasia Maroteaux type (AMDM).

Shapiro, Frederic / Barone, Lauren / Johnson, Andrew / Flynn, Evelyn

BMC musculoskeletal disorders

2014 Volume 15, Page(s) 347

Abstract: Background: The cn/cn dwarf mouse is caused by a loss-of-function mutation in the natriuretic peptide receptor 2 (NPR-2) gene which helps positively regulate endochondral longitudinal bone growth. The gene mutation corresponds to that in the human ... ...

Abstract	Background: The cn/cn dwarf mouse is caused by a loss-of-function mutation in the natriuretic peptide receptor 2 (NPR-2) gene which helps positively regulate endochondral longitudinal bone growth. The gene mutation corresponds to that in the human skeletal dysplasia Acromesomelic Dysplasia Maroteaux type (AMDM). This study assesses histomorphometric, ultrastructural and radiographic correlates of the growth abnormality. Methods: Ten litters of cn/cn and cn/+littermates at ages ranging from 2.5 to 6.5 weeks were studied by skeletal radiographs, histomorphometry and physeal ultrastructure. Skeletal radiographs were done on 2 cn/cn and 2 cn/+littermates at 5 weeks of age. Humeral, femoral, and tibial lengths were measured from 34 intact bones (17 cn/cn, 17 cn/+) at 2.5 to 6.5 weeks. Growth plate histomorphometry in 50 bones (26 cn/cn and 24 cn/+) determined the hypertrophic zone/entire physeal cartilage ratios in 204 sections (87 cn/+, 117 cn/cn) at 3 time periods (2.5-3, 4-4.5, and 6-6.5 weeks). Electron microscopy assessed 6 cn/cn and 6 cn/+age and site-matched physeal cartilage. Results: Cn/cn mice were two thirds the size of the cn/+. Cn/cn bones were normal in shape or only minimally deformed except for the radius with mid-diaphyseal bowing. Length ratios of cn/cn humeri, femurs, and tibias were a mean of 0.65 (± 0.03, n = 34, 17 ratios) compared to cn/+bones. The main physeal abnormality was a markedly shortened hypertrophic zone with the ratio of hypertrophic zone to entire physis 0.17 (± 0.063) in the cn/cn and 0.30 (± 0.052) in the cn/+mice. Ratio assessments were similar comparing humeral, femoral, and tibial growth plates as were ratios from each of the 3 time periods. Ultrastructural assessments from the resting zone to the lower hypertrophic zone-metaphyseal junction showed no specific individual cell abnormalities in cn/cn compared to cn/+physes. Conclusions: The disorder causes a shortened physeal hypertrophic zone but normal ultrastructure of cn/cn chondrocytes points to abnormality primarily affecting the hypertrophic zone rather than a structural cell or matrix synthesis problem.
MeSH term(s)	Animals ; Body Weight ; Bone Diseases, Developmental/diagnostic imaging ; Bone Diseases, Developmental/pathology ; Bone and Bones/diagnostic imaging ; Bone and Bones/pathology ; Bone and Bones/ultrastructure ; Chondrocytes/ultrastructure ; Disease Models, Animal ; Epiphyses/pathology ; Epiphyses/ultrastructure ; Femur/diagnostic imaging ; Femur/pathology ; Femur/ultrastructure ; Growth Plate/pathology ; Growth Plate/ultrastructure ; Humans ; Humerus/diagnostic imaging ; Humerus/pathology ; Humerus/ultrastructure ; Mice ; Mice, Mutant Strains ; Radiography ; Tibia/diagnostic imaging ; Tibia/pathology ; Tibia/ultrastructure
Language	English
Publishing date	2014-10-15
Publishing country	England
Document type	Journal Article
ISSN	1471-2474
ISSN (online)	1471-2474
DOI	10.1186/1471-2474-15-347
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Article ; Online: T Cell-Specific Adaptor Protein Regulates Mitochondrial Function and CD4

Wedel, Johannes / Stack, Maria P / Seto, Tatsuichiro / Sheehan, Matthew M / Flynn, Evelyn A / Stillman, Isaac E / Kong, Sek Won / Liu, Kaifeng / Briscoe, David M

Journal of immunology (Baltimore, Md. : 1950)

2019 Volume 203, Issue 8, Page(s) 2328–2338

Abstract: The T cell-specific adaptor protein (TSAd), encoded by ... ...

Abstract	The T cell-specific adaptor protein (TSAd), encoded by the
MeSH term(s)	Adaptor Proteins, Signal Transducing/deficiency ; Adaptor Proteins, Signal Transducing/metabolism ; Adoptive Transfer ; Animals ; CD4-Positive T-Lymphocytes/cytology ; CD4-Positive T-Lymphocytes/immunology ; Cell Proliferation ; Cells, Cultured ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism ; Transplantation
Chemical Substances	Adaptor Proteins, Signal Transducing ; Sh2d2a protein, mouse
Language	English
Publishing date	2019-09-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1801604
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Article ; Online: Molecular differentiation in epiphyseal and physeal cartilage. Prominent role for gremlin in maintaining hypertrophic chondrocytes in epiphyseal cartilage.

Shapiro, Frederic / Flynn, Evelyn / Calicchio, Monica L

Biochemical and biophysical research communications

2009 Volume 390, Issue 3, Page(s) 570–576

Abstract: We have studied hypertrophic and immediately adjacent pre-hypertrophic chondrocytes at the same stage of histologic development in 7 day old post-natal Balb/C mouse physes and epiphyses. Laser capture microdissection (LCM) and GeneChip microarray ... ...

Abstract	We have studied hypertrophic and immediately adjacent pre-hypertrophic chondrocytes at the same stage of histologic development in 7 day old post-natal Balb/C mouse physes and epiphyses. Laser capture microdissection (LCM) and GeneChip microarray analysis compared the molecular composition of the two hypertrophic chondrocyte regions. Molecules upregulated in dramatically higher levels in the epiphysis were gremlin (58-fold), epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (25-fold), and frizzled related protein (6.4-fold and 5.7-fold). Molecules upregulated in higher levels in the physis were proline arginine-rich end leucine-rich repeat protein (PRELP) (15.6-fold), pyrophosphatase (inorganic) 1 (10-fold) and hedgehog-interacting protein (7.3-fold). Immunocytochemistry for gremlin confirmed specific localization patterns. This study indicates a critical site-specific role for hypertrophic chondrocytes with different synthesis patterns in separate regions even though they appear structurally the same and are at the same stage of development.
MeSH term(s)	Animals ; Cell Differentiation ; Chondrocytes/cytology ; Chondrocytes/metabolism ; Chondrocytes/physiology ; Extracellular Matrix Proteins/biosynthesis ; Glycoproteins/biosynthesis ; Growth Plate/cytology ; Growth Plate/growth & development ; Growth Plate/metabolism ; Intercellular Signaling Peptides and Proteins/biosynthesis ; Intercellular Signaling Peptides and Proteins/physiology ; Mice ; Mice, Inbred BALB C ; Proteins/metabolism ; Up-Regulation
Chemical Substances	Extracellular Matrix Proteins ; Glycoproteins ; Grem1 protein, mouse ; Intercellular Signaling Peptides and Proteins ; Prelp protein, mouse ; Proteins ; WD repeat containing planar cell polarity effector
Language	English
Publishing date	2009-10-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2009.10.006
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Article ; Online: DEPTOR regulates vascular endothelial cell activation and proinflammatory and angiogenic responses.

Bruneau, Sarah / Nakayama, Hironao / Woda, Craig B / Flynn, Evelyn A / Briscoe, David M

Blood

2013 Volume 122, Issue 10, Page(s) 1833–1842

Abstract: The maintenance of normal tissue homeostasis and the prevention of chronic inflammatory disease are dependent on the active process of inflammation resolution. In endothelial cells (ECs), proinflammation results from the activation of intracellular ... ...

Abstract	The maintenance of normal tissue homeostasis and the prevention of chronic inflammatory disease are dependent on the active process of inflammation resolution. In endothelial cells (ECs), proinflammation results from the activation of intracellular signaling responses and/or the inhibition of endogenous regulatory/pro-resolution signaling networks that, to date, are poorly defined. In this study, we find that DEP domain containing mTOR interacting protein (DEPTOR) is expressed in different microvascular ECs in vitro and in vivo, and using a small interfering RNA (siRNA) knockdown approach, we find that it regulates mammalian target of rapamycin complex 1 (mTORC1), extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription 1 activation in part through independent mechanisms. Moreover, using limited gene arrays, we observed that DEPTOR regulates EC activation including mRNA expression of the T-cell chemoattractant chemokines CXCL9, CXCL10, CXCL11, CX3CL1, CCL5, and CCL20 and the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (P < .05). DEPTOR siRNA-transfected ECs also bound increased numbers of peripheral blood mononuclear cells (P < .005) and CD3+ T cells (P < .005) in adhesion assays in vitro and had increased migration and angiogenic responses in spheroid sprouting (P < .01) and wound healing (P < .01) assays. Collectively, these findings define DEPTOR as a critical upstream regulator of EC activation responses and suggest that it plays an important role in endogenous mechanisms of anti-inflammation and pro-resolution.
MeSH term(s)	Cell Adhesion Molecules/genetics ; Cell Adhesion Molecules/metabolism ; Cell Communication/genetics ; Chemokines/genetics ; Chemokines/metabolism ; Gene Expression Regulation ; HEK293 Cells ; Human Umbilical Vein Endothelial Cells/enzymology ; Human Umbilical Vein Endothelial Cells/pathology ; Humans ; Inflammation/genetics ; Inflammation/pathology ; Inflammation Mediators/metabolism ; Intracellular Signaling Peptides and Proteins ; Mechanistic Target of Rapamycin Complex 1 ; Mechanistic Target of Rapamycin Complex 2 ; Mitogen-Activated Protein Kinase 3/metabolism ; Multiprotein Complexes/metabolism ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/pathology ; Protein Binding ; STAT1 Transcription Factor/metabolism ; Signal Transduction/genetics ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Cell Adhesion Molecules ; Chemokines ; Inflammation Mediators ; Intracellular Signaling Peptides and Proteins ; Multiprotein Complexes ; STAT1 Transcription Factor ; STAT1 protein, human ; DEPTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24)
Language	English
Publishing date	2013-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2013-03-488486
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In stock of ZB MED Cologne/Königswinter

Order via subito