References of "Schneider, Jochen 50003032"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailShort-term akt activation in cardiac muscle cells improves contractile function in failing hearts
Shiojima, I.; Schiekofer, S.; Schneider, Jochen UL et al

in American Journal of Pathology (2012), 181(6), 1969-76

Akt is a serine/threonine protein kinase that is activated by a variety of growth factors or cytokines in a phosphatidylinositol 3-kinase-dependent manner. By using a conditional transgenic system in ... [more ▼]

Akt is a serine/threonine protein kinase that is activated by a variety of growth factors or cytokines in a phosphatidylinositol 3-kinase-dependent manner. By using a conditional transgenic system in which Akt signaling can be turned on or off in the adult heart, we previously showed that short-term Akt activation induces a physiological form of cardiac hypertrophy with enhanced coronary angiogenesis and maintained contractility. Here we tested the hypothesis that induction of physiological hypertrophy by short-term Akt activation might improve contractile function in failing hearts. When Akt signaling transiently was activated in murine hearts with impaired contractility, induced by pressure overload or doxorubicin treatment, contractile dysfunction was attenuated in both cases. Importantly, improvement of contractility was observed before the development of cardiac hypertrophy, indicating that Akt activation improves contractile function independently of its growth-promoting effects. To gain mechanistic insights into Akt-mediated positive inotropic effects, transcriptional profiles in the heart were determined in a pressure overload-induced heart failure model. Biological network analysis of differentially expressed transcripts revealed significant alterations in the expression of genes associated with cell death, and these alterations were reversed by short-term Akt activation. Thus, short-term Akt activation improves contractile function in failing hearts. This beneficial effect of Akt on contractility is hypertrophy-independent and may be mediated in part by inhibition of cell death associated with heart failure. [less ▲]

Detailed reference viewed: 116 (0 UL)
Full Text
Peer Reviewed
See detailHedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment.
Heller, E. UL; Hurchla, M. A.; Xiang, J. et al

in Trends in Cancer Research (2012), 72(4), 897-907

Hedgehog (Hh) signaling is implicated in bone development and cellular transformation. Here we demonstrate that inhibition of Hh pathway activity inhibits tumor growth through effects on the ... [more ▼]

Hedgehog (Hh) signaling is implicated in bone development and cellular transformation. Here we demonstrate that inhibition of Hh pathway activity inhibits tumor growth through effects on the microenvironment. Pharmacological inhibition of the Hh effector Smoothened (Smo) increased trabecular bone in vivo and inhibited osteoclastogenesis in vitro. In addition, enhanced Hh signaling due to heterozygosity of the Hh inhibitory receptor Patched (Ptch1+/-) increased bone resorption, suggesting direct regulation of osteoclast activity by the Hh pathway. Ptch1+/- mice had increased bone metastatic and subcutaneous tumor growth, suggesting that increased Hh activation in host cells promoted tumor growth. Subcutaneous growth of Hh-resistant tumor cells was inhibited by LDE225, a novel orally bioavailable Smo antagonist, consistent with effects on tumor microenvironment. Knockdown of the Hh ligand Sonic Hh (SHH) in these cells decreased subcutaneous tumor growth and decreased stromal cell production of IL-6, indicating that tumor-derived Hh ligands stimulated tumor growth in a paracrine fashion. Together our findings demonstrate that inhibition of the Hh pathway can reduce tumor burden, regardless of tumor Hh responsiveness, through effects on tumor cells, osteoclasts and stromal cells within the tumor microenvironment. Hh may be a promising therapeutic target for solid cancers and bone metastases. [less ▲]

Detailed reference viewed: 118 (0 UL)
Full Text
Peer Reviewed
See detailThe ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling
Su, X.; Floyd, D. H.; Hughes, A. et al

in Journal of Clinical Investigation (2012), 122(10), 3579-3592

The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac ... [more ▼]

The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12-/- OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12-/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbβ3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β3 gene knockout (Itgb3-/-) OCs, but its effects were substantially blunted in P2ry12-/- OCs. In vivo, P2ry12-/- mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss. [less ▲]

Detailed reference viewed: 161 (0 UL)
Full Text
Peer Reviewed
See detailAdiponectin Fails in Improving Angiogenic Repair in Streptozocin-Treated or Lepr db/db Mice after Hind Limb Ischemia
Belisle, Kurt UL; Andrassy, Martin; Schneider, Jochen UL et al

in International Scholarly Research Notices (2012), 2012

Type 1 and 2 diabetes carry risk factors for the development of microvascular diseases with associated impairment of angiogenic repair. Here, we investigated whether adiponectin, an adipocyte-specific ... [more ▼]

Type 1 and 2 diabetes carry risk factors for the development of microvascular diseases with associated impairment of angiogenic repair. Here, we investigated whether adiponectin, an adipocyte-specific adipocytokine with antiatherosclerotic and antidiabetic properties, regulates angiogenic repair in response to tissue ischemia in Leprdb/db and streptozocin-treated diabetic mouse models. Methods. Adenoviral vectors containing the gene for β-galactosidase, full-length mouse adiponectin, and dominant-negative AMPKα2 were used in streptozocin-treated male Leprdb/db mice, after which hind limb blood flow was measured using a laser doppler blood flow analyzer. Results. The angiogenic repair of ischemic hind limbs was impaired in both streptozocin-treated and Leprdb/db mice compared to wild-type mice as evaluated by laser doppler flow and capillary density analyses. Adenovirus-mediated administration of adiponectin accelerated angiogenic repair after hind limb ischemia in WT mice, but not in Leprdb/db mice or mice treated with streptozocin. In vitro experiments using HUVECs highlighted the antiapoptotic and proangiogenic properties of adiponectin but could not demonstrate accelerated differentiation of endothelial cells into tube- like structures at elevated glucose levels. Conclusions. External administration of adiponectin at elevated glucose levels may not be useful in the treatment of diabetes mellitus-related vascular deficiency diseases. [less ▲]

Detailed reference viewed: 130 (2 UL)
Full Text
Peer Reviewed
See detailAn Unknown Input Fractional-Order Observer Design for Fractional-Order Glucose-Insulin System
Ndoye, Ibrahima UL; Voos, Holger UL; Darouach, Mohamed et al

in IEEE EMBS Conference on Biomedical Engineering and Sciences, Malaysia, 17th - 19th December, 2012 (2012)

In this paper, we introduce fractional-order derivatives into a generalized minimal model of glucose-insulin. A fractional-order state observer is designed for estimating the structure of a blood glucose ... [more ▼]

In this paper, we introduce fractional-order derivatives into a generalized minimal model of glucose-insulin. A fractional-order state observer is designed for estimating the structure of a blood glucose-insulin with glucose rate disturbance to show the complete dynamics of the glucose-insulin system where the fractional-order \alpha belonging to 0<\alpha<1. A nonlinear fractional-order unknown input observer strategy is used where the glucose rate disturbance is considered as an unknown input to the perspective dynamical system. The developed method provides the observer estimation algorithm for a glucose-insulin system with unknown time-varying glucose rate disturbance. The stability analysis of the fractional-order error system is completed and showed that the fractional-order observer design is as stable as their integer-order counterpart and guarantees the best convergence of the estimation error. Finally, numerical simulations are given to illustrate the effectiveness of the proposed method. [less ▲]

Detailed reference viewed: 179 (5 UL)
Full Text
Peer Reviewed
See detailIntegrins and bone metastasis: integrating tumor cell and stromal cell interactions
Schneider, Jochen UL; Amend, S. R.; Weilbaecher, K. N.

in BONE (2011), 48(1), 54-65

Integrins on both tumor cells and the supporting host stromal cells in bone (osteoclasts, new blood vessels, inflammatory cells, platelets and bone marrow stromal cells) play key roles in enhancing bone ... [more ▼]

Integrins on both tumor cells and the supporting host stromal cells in bone (osteoclasts, new blood vessels, inflammatory cells, platelets and bone marrow stromal cells) play key roles in enhancing bone metastasis. Tumor cells localize to specific tissues through integrin-mediated contacts with extracellular matrix and stromal cells. Integrin expression and signaling are perturbed in cancer cells, allowing them to "escape" from cell-cell and cell-matrix tethers, invade, migrate and colonize within new tissues and matrices. Integrin signaling through αvβ3 and VLA-4 on tumor cells can promote tumor metastasis to and proliferation in the bone microenvironment. Osteoclast (OC) mediated bone resorption is a critical component of bone metastasis and can promote tumor growth in bone and αvβ3 integrins are critical to OC function and development. Tumors in the bone microenvironment can recruit new blood vessel formation, platelets, pro-tumor immune cells and bone marrow stromal cells that promote tumor growth and invasion in bone. Integrins and their ligands play critical roles in platelet aggregation (αvβ3 and αIIbβ3), hematopoietic cell mobilization (VLA-4 and osteopontin), neoangiogenesis (αvβ3, αvβ5, α6β4, and β1 integrin) and stromal function (osteopontin and VLA-4). Integrins are involved in the pathogenesis of bone metastasis at many levels and further study to define integrin dysregulation by cancer will yield new therapeutic targets for the prevention and treatment of bone metastasis. [less ▲]

Detailed reference viewed: 123 (1 UL)
Full Text
Peer Reviewed
See detailPPARγ population shift produces disease-related changes in molecular networks associated with metabolic syndrome
Jurkowski, Wiktor UL; Roomp, Kirsten UL; Crespo, Isaac UL et al

in Cell Death and Disease (2011), 2(8), 192

Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipocyte differentiation and has an important role in metabolic syndrome. Phosphorylation of the receptor's ligand-binding ... [more ▼]

Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipocyte differentiation and has an important role in metabolic syndrome. Phosphorylation of the receptor's ligand-binding domain at serine 273 has been shown to change the expression of a large number of genes implicated in obesity. The difference in gene expression seen when comparing wild-type phosphorylated with mutant non-phosphorylated PPARγ may have important consequences for the cellular molecular network, the state of which can be shifted from the healthy to a stable diseased state. We found that a group of differentially expressed genes are involved in bi-stable switches and form a core network, the state of which changes with disease progression. These findings support the idea that bi-stable switches may be a mechanism for locking the core gene network into a diseased state and for efficiently propagating perturbations to more distant regions of the network. A structural analysis of the PPARγ-RXRα dimer complex supports the hypothesis of a major structural change between the two states, and this may represent an important mechanism leading to the differential expression observed in the core network. [less ▲]

Detailed reference viewed: 267 (18 UL)
Peer Reviewed
See detailDe Novo Lipogenesis Maintains Vascular Homeostasis through Endothelial Nitric-oxide Synthase (eNOS) Palmitoylation
Wei, Xiaochao; Schneider, Jochen UL; Shenouda, Sherene M. et al

in Journal of Biological Chemistry (2011), 286(4), 2933-2945

Endothelial dysfunction leads to lethal vascular complications in diabetes and related metabolic disorders. Here, we demonstrate that de novo lipogenesis, an insulin-dependent process driven by the ... [more ▼]

Endothelial dysfunction leads to lethal vascular complications in diabetes and related metabolic disorders. Here, we demonstrate that de novo lipogenesis, an insulin-dependent process driven by the multifunctional enzyme fatty-acid synthase (FAS), maintains endothelial function by targeting endothelial nitric-oxide synthase (eNOS) to the plasma membrane. In mice with endothelial inactivation of FAS (FASTie mice), eNOS membrane content and activity were decreased. eNOS and FAS were physically associated; eNOS palmitoylation was decreased in FAS-deficient cells, and incorporation of labeled carbon into eNOS-associated palmitate was FAS-dependent. FASTie mice manifested a proinflammatory state reflected as increases in vascular permeability, endothelial inflammatory markers, leukocyte migration, and susceptibility to LPS-induced death that was reversed with an NO donor. FAS-deficient endothelial cells showed deficient migratory capacity, and angiogenesis was decreased in FASTie mice subjected to hindlimb ischemia. Insulin induced FAS in endothelial cells freshly isolated from humans, and eNOS palmitoylation was decreased in mice with insulin-deficient or insulin-resistant diabetes. Thus, disrupting eNOS bioavailability through impaired lipogenesis identifies a novel mechanism coordinating nutritional status and tissue repair that may contribute to diabetic vascular disease. [less ▲]

Detailed reference viewed: 129 (0 UL)
Peer Reviewed
See detailNew hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis
Chakravarthy, M. V.; Pan, Z.; Zhu, Y. et al

in Cell Metabolism (2005), 1(5), 309-22

De novo lipogenesis is an energy-expensive process whose role in adult mammals is poorly understood. We generated mice with liver-specific inactivation of fatty-acid synthase (FAS), a key lipogenic enzyme ... [more ▼]

De novo lipogenesis is an energy-expensive process whose role in adult mammals is poorly understood. We generated mice with liver-specific inactivation of fatty-acid synthase (FAS), a key lipogenic enzyme. On a zero-fat diet, FASKOL (FAS knockout in liver) mice developed hypoglycemia and fatty liver, which were reversed with dietary fat. These phenotypes were also observed after prolonged fasting, similarly to fasted PPARalpha-deficiency mice. Hypoglycemia, fatty liver, and defects in expression of PPARalpha target genes in FASKOL mice were corrected with a PPARalpha agonist. On either zero-fat or chow diet, FASKOL mice had low serum and hepatic cholesterol levels with elevated SREBP-2, decreased HMG-CoA reductase expression, and decreased cholesterol biosynthesis; these were also corrected with a PPARalpha agonist. These results suggest that products of the FAS reaction regulate glucose, lipid, and cholesterol metabolism by serving as endogenous activators of distinct physiological pools of PPARalpha in adult liver [less ▲]

Detailed reference viewed: 92 (0 UL)