References of "Schneider, Jochen 50003032"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailStatic Output Feedback Stabilization of Nonlinear 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)

Diabetes is a long-term disease during which the body's production and use of the insulin are impaired, causing glucose concentration level to increase in the bloodstream. The blood glucose dynamics is ... [more ▼]

Diabetes is a long-term disease during which the body's production and use of the insulin are impaired, causing glucose concentration level to increase in the bloodstream. The blood glucose dynamics is described using the generalized minimal model structure for the intravenously infused insulin blood glucose, which can represent a wide variety of diabetic patients. In this paper, it is an attempt to incorporate fractional-order derivative into the mathematical minimal model of glucose-insulin system dynamics and it is still an interesting challenge to determine, mathematically, how the order of a fractional differential system affects the dynamics of system. The paper presents the asymptotical stabilization problem of nonlinear fractional-order glucose insulin systems. A static output feedback control is considered for the problem. Sufficient conditions for the asymptotical stabilization of the nonlinear fractional-order glucose-insulin system are derived in terms of linear matrix inequalities (LMIs) formulation by using the fractional Lyapunov direct method where the fractional-order \alpha belonging to 0<\alpha<1. Finally, numerical simulations are carried out to illustrate our proposed results. These numerical simulations show that the nonlinear fractional-order glucose-insulin systems are, at least, as stable as their integer-order counterpart. [less ▲]

Detailed reference viewed: 243 (5 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: 150 (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: 109 (0 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: 113 (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: 251 (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: 118 (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: 80 (0 UL)