Decreased Liver Kinase B1 Expression and Impaired Angiogenesis in a Murine Model of Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is characterized by impaired lung alveolar and vascular growth. We investigated the hypothesis that neonatal exposure to hyperoxia leads to persistent BPD phenotype caused by decreased expression of liver kinase B1 (LKB1), a key regulator of mitochondrial function. We exposed mouse pups from Postnatal Day (P)1 through P10 to 21% or 75% oxygen.

Aberrant PGC-1α signaling in a lamb model of persistent pulmonary hypertension of the newborn.

Background: Persistent Pulmonary Hypertension of the Newborn (PPHN) is characterized by elevated pulmonary vascular resistance (PVR), resulting in hypoxemia. Impaired angiogenesis contributes to high PVR. Pulmonary artery endothelial cells (PAECs) in PPHN exhibit decreased mitochondrial respiration and angiogenesis.

Fetal pulmonary hypertension: dysregulated microRNA-34c-Notch1 axis contributes to impaired angiogenesis in an ovine model.

Background: Persistent pulmonary hypertension of the newborn (PPHN) occurs when pulmonary vascular resistance (PVR) fails to decrease at birth. Decreased angiogenesis in the lung contributes to the persistence of high PVR at birth. MicroRNAs (miRNAs) regulate gene expression through transcript binding and degradation.

NOGOB receptor deficiency increases cerebrovascular permeability and hemorrhage via impairing histone acetylation-mediated CCM1/2 expression.

The loss function of cerebral cavernous malformation (CCM) genes leads to most CCM lesions characterized by enlarged leaking vascular lesions in the brain. Although we previously showed that NOGOB receptor (NGBR) knockout in endothelial cells (ECs) results in cerebrovascular lesions in the mouse embryo, the molecular mechanism by which NGBR regulates CCM1/2 expression has not been elucidated. Here, we show that genetic depletion of Ngbr in ECs at both postnatal and adult stages results in CCM1/2 expression deficiency and cerebrovascular lesions such as enlarged vessels, blood-brain-barrier hyperpermeability, and cerebral hemorrhage.

Decreased Cyclic Guanosine Monophosphate-Protein Kinase G Signaling Impairs Angiogenesis in a Lamb Model of Persistent Pulmonary Hypertension of the Newborn.

Impaired angiogenesis function in pulmonary artery endothelial cells (PAEC) contributes to persistent pulmonary hypertension of the newborn (PPHN). Decreased nitric oxide (NO) amounts in PPHN lead to impaired mitochondrial biogenesis and angiogenesis in the lung; the mechanisms remain unclear. We hypothesized that decreased cyclic guanosine monophosphate (cGMP)-PKG (protein kinase G) signaling downstream of NO leads to decreased mitochondrial biogenesis and angiogenesis in PPHN.

Decreased AMP-activated protein kinase (AMPK) function and protective effect of metformin in neonatal rat pups exposed to hyperoxia lung injury.

We investigated the hypothesis that exposure of lungs at the saccular stage of development to hyperoxia leads to persistent growth arrest and dysfunction of 5'AMP-activated protein kinase (AMPK), a key energy sensor in the cell. We exposed neonatal rat pups from postnatal day 1- day 10 (P1-P10) to ≥90% oxygen or control normoxia. Pups were euthanized at P4 or P10 or recovered in normoxia until euthanasia at P21.

AMP-Kinase Dysfunction Alters Notch Ligands to Impair Angiogenesis in Neonatal Pulmonary Hypertension.

Decreased angiogenesis contributes to persistent pulmonary hypertension of the newborn (PPHN); mechanisms remain unclear. AMPK (5'AMP activated protein kinase) is a key regulator of cell metabolism. We investigated the hypothesis that a decrease in AMPK function leads to mitochondrial dysfunction and altered balance of notch ligands delta-like 4 (DLL4) and Jagged 1 (Jag1) to impair angiogenesis in PPHN.

Adherence to endocrine therapy among Chinese patients with breast cancer: current status and recommendations for improvement.

Background: Postoperative endocrine therapy is known to reduce recurrence and mortality in patients with estrogen receptor (ER)- or progestogen receptor (PR)-positive breast cancer. Correlates and determinants of compliance with endocrine therapy among Chinese patients with breast cancer are not known. The aim of this study was to elucidate the efficacy and adherence of endocrine therapy in China and suggest effective improvements on the adherence.

Nogo-B receptor increases the resistance of estrogen receptor positive breast cancer to paclitaxel.

Intrinsic or acquired chemoresistance is a hurdle in oncology. Only 7%-16% of estrogen receptor α (ERα) positive breast cancer cases achieve a pathological complete response (pCR) after neo-adjuvant chemotherapy. Nogo-B receptor (NgBR) is a cell surface receptor that binds farnesylated Ras and promotes Ras translocation to the plasma membrane.

Domain Mapping of Heat Shock Protein 70 Reveals That Glutamic Acid 446 and Arginine 447 Are Critical for Regulating Superoxide Dismutase 2 Function.

Stress-inducible heat shock protein 70 (hsp70) interacts with superoxide dismutase 2 (SOD2) in the cytosol after synthesis to transfer the enzyme to the mitochondria for subsequent activation. However, the structural basis for this interaction remains to be defined. To map the SOD2-binding site in hsp70, mutants of hsp70 were made and tested for their ability to bind SOD2.

Nogo-B receptor deficiency increases liver X receptor alpha nuclear translocation and hepatic lipogenesis through an adenosine monophosphate-activated protein kinase alpha-dependent pathway.

Unlabelled: Nogo-B receptor (NgBR) was identified as a specific receptor for binding Nogo-B and is essential for the stability of Niemann-Pick type C2 protein (NPC2) and NPC2-dependent cholesterol trafficking. Here, we report that NgBR expression levels decrease in the fatty liver and that NgBR plays previously unrecognized roles in regulating hepatic lipogenesis through NPC2-independent pathways. To further elucidate the pathophysiological role of NgBR in mammals, we generated NgBR liver-specific knockout mice and investigated the roles of NgBR in hepatic lipid homeostasis.

Nogo-B receptor deficiency causes cerebral vasculature defects during embryonic development in mice.

Nogo-B receptor (NgBR) was identified as a receptor specific for Nogo-B. Our previous work has shown that Nogo-B and its receptor (NgBR) are essential for chemotaxis and morphogenesis of endothelial cells in vitro and intersomitic vessel formation via Akt pathway in zebrafish. Here, we further demonstrated the roles of NgBR in regulating vasculature development in mouse embryo and primitive blood vessel formation in embryoid body culture systems, respectively.

Nogo-B Receptor Modulates Pulmonary Artery Smooth Muscle Cell Function in Developing Lungs.

Nogo-B and its receptor (NgBR) are involved in blood vessel growth in developing lungs, but their role in pulmonary artery smooth muscle cell (PASMC) growth is unknown. We hypothesized that NgBR regulates growth of PASMCs by modulating the function of endoplasmic reticulum (ER) and formation of reactive oxygen species (ROS). In utero constriction of the ductus arteriosus created pulmonary hypertension in fetal lambs (hypertensive fetal lamb [HTFL]).

Nogo-B receptor modulates angiogenesis response of pulmonary artery endothelial cells through eNOS coupling.

Nogo-B, a reticulon-4 isoform, modulates the motility and adhesion of vascular endothelial cells after binding to its receptor, Nogo-B receptor (NgBR). Nogo-B/NgBR pathway contributes to vascular remodeling and angiogenesis, but the role of this pathway in the angiogenesis of developing lungs remains unknown. We previously reported that angiogenesis function of pulmonary artery endothelial cells (PAECs) is impaired by increased reactive oxygen species formation in a fetal lamb model of intrauterine pulmonary hypertension (IPH).

Inducible HSP70 regulates superoxide dismutase-2 and mitochondrial oxidative stress in the endothelial cells from developing lungs.

Superoxide dismutase 2 (SOD-2) is synthesized in the cytosol and imported into the mitochondrial matrix, where it is activated and functions as the primary antioxidant for cellular respiration. The specific mechanisms that target SOD-2 to the mitochondria remain unclear. We hypothesize that inducible heat shock protein 70 (iHSP70) targets SOD-2 to the mitochondria via a mechanism facilitated by ATP, and this process is impaired in persistent pulmonary hypertension of the newborn (PPHN).

Zinc binding ligands and cellular zinc trafficking: apo-metallothionein, glutathione, TPEN, proteomic zinc, and Zn-Sp1.

Many cell types contain metal-ion unsaturated metallothionein (MT). Considering the Zn(2+) binding affinity of metallothionein, the existence of this species in the intracellular environment constitutes a substantial "thermodynamic sink". Indeed, the mM concentration of glutathione may be thought of in the same way.