Antiatherogenicity of extra virgin olive oil and its enrichment with green tea polyphenols in the atherosclerotic apolipoprotein-E-deficient mice: enhanced macrophage cholesterol efflux.

The antiatherogenic properties of extra virgin olive oil (EVOO) enriched with green tea polyphenols (GTPPs; hereafter called EVOO-GTPP), in comparison to EVOO, were studied in the atherosclerotic apolipoprotein-E-deficient (E0) mice. E0 mice (eight mice in each group) consumed EVOO or EVOO-GTPP (7 microl/mouse/day, for 2 months) by gavage feeding. The placebo group received only water.

Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response.

Due to its channel-like properties, the peripheral-type benzodiazepine receptor (PBR) has been renamed the translocator protein (TSPO). In eukaryotes, the TSPO is primarily located in the outer mitochondrial membrane. In prokaryotes, it is found in the cell membrane.

Urokinase plasminogen activator (uPA) stimulates cholesterol biosynthesis in macrophages through activation of SREBP-1 in a PI3-kinase and MEK-dependent manner.

Urokinase plasminogen activator (uPA) is expressed in human atherosclerotic lesions, predominantly in macrophages, and contributes to atherosclerosis progression. Since atherogenesis is characterized by the formation of cholesterol-loaded macrophage foam cells, we questioned whether uPA atherogenicity may involve macrophage cholesterol accumulation, and by what mechanisms. uPA increased cellular cholesterol content by 44% (mainly unesterified cholesterol) in THP-1 macrophages, and this effect was inhibited by statins.

Ox-LDL induces monocyte-to-macrophage differentiation in vivo: Possible role for the macrophage colony stimulating factor receptor (M-CSF-R).

Monocyte-to-macrophage differentiation and LDL oxidation play a pivotal role in early atherogenesis. We thus questioned possible mechanisms for oxidized LDL (Ox-LDL)-induced monocyte-to-macrophage differentiation in vivo. Mouse peritoneal mononuclear cells, that were isolated 1, 2, or 3 days after Ox-LDL intraperitoneal injection, gradually exhibited the characteristic macrophage morphology, along with the expression of the cell-surface antigen CD11b.

Additional sex combs affects antennal development by means of spatially restricted repression of Antp and wg.

Additional sex combs (Asx) is thought to function in protein complexes of both the Trithorax and Polycomb groups, but very little is known about its developmental roles. Here, we present a detailed analysis of Asx's role in antennal development. We show that loss of Asx in the antennal disc causes a complex phenotype, which consists of distal antenna-to-leg transformations and outgrowth of ectopic leg-like appendages from the Dpp-expressing domain of the disc.

In vitro and ex vivo suppression by aminoglycosides of PCDH15 nonsense mutations underlying type 1 Usher syndrome.

Type 1 Usher syndrome (USH1) is a recessively inherited condition, characterized by profound prelingual deafness, vestibular areflexia, and prepubertal onset of retinitis pigmentosa (RP). While the auditory component of USH1 can be treated by cochlear implants, to date there is no effective treatment for RP. USH1 can be caused by mutations in each of at least six genes.

Anti-oxidant and anti-atherogenic properties of liposomal glutathione: studies in vitro, and in the atherosclerotic apolipoprotein E-deficient mice.

Liposomal glutathione, but not the control liposomes (with no glutathione), dose-dependently inhibited copper ion-induced low density lipoprotein (LDL) and HDL oxidation. As peroxidase activity was found to be present in both LDL and HDL, it has contributed to the anti-oxidative effects of liposomal glutathione. In-vitro, no significant effect of liposomal glutathione on J774 A.

Identification and selection of cardiomyocytes during human embryonic stem cell differentiation.

Human embryonic stem cells (hESC) are pluripotent lines that can differentiate in vitro into cell derivatives of all three germ layers, including cardiomyocytes. Successful application of these unique cells in the areas of cardiovascular research and regenerative medicine has been hampered by difficulties in identifying and selecting specific cardiac progenitor cells from the mixed population of differentiating cells. We report the generation of stable transgenic hESC lines, using lentiviral vectors, and single-cell clones that express a reporter gene (eGFP) under the transcriptional control of a cardiac-specific promoter (the human myosin light chain-2V promoter).

SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK.

ITK (IL-2-inducible T cell kinase), a Tec family protein tyrosine kinase (PTK), is one of three PTKs required for T cell antigen receptor (TCR)-induced activation of phospholipase C-gamma1 (PLC-gamma1). Like Src and Abl family PTKs, ITK adopts an inactive, "closed" conformation, and its conversion to the active conformation is not well understood, nor have its direct substrates been identified. In a side-by-side comparison of ITK and ZAP-70 (zeta chain-associated protein kinase of 70 kDa), ITK efficiently phosphorylated Y(783) and Y(775) of PLC-gamma1, two phosphorylation sites that are critical for its activation, whereas ZAP-70 did not.

Autophosphorylation-dependent degradation of Pak1, triggered by the Rho-family GTPase, Chp.

The Paks (p21-activated kinases) Pak1, Pak2 and Pak3 are among the most studied effectors of the Rho-family GTPases, Rac, Cdc42 (cell division cycle 42) and Chp (Cdc42 homologous protein). Pak kinases influence a variety of cellular functions, but the process of Pak down-regulation, following activation, is poorly understood. In the present study, we describe for the first time a negative-inhibitory loop generated by the small Rho-GTPases Cdc42 and Chp, resulting in Pak1 inhibition.

Renal slit diaphragm--the open zipper and the failing heart.

Inherited forms of proteinuria constitute a rare and heterogeneous group of diseases, the most prominent of which is glomerular dysfunction, which leads to proteinuria. Investigation of the genetic background underlying these diseases has provided significant data on the normal operation of the glomerular filter. Among the different components of the glomerulus, the podocyte slit diaphragm is considered the main source for genetically derived protein alteration, which leads in turn to proteinuria.

Macrophage paraoxonase 2 (PON2) expression is up-regulated by pomegranate juice phenolic anti-oxidants via PPAR gamma and AP-1 pathway activation.

Paraoxonase 2 (PON2), a member of the paraoxonase gene family, was shown to protect macrophages against oxidative stress. Pomegranate juice (PJ), which contains potent polyphenol anti-oxidants, exhibits similar effects. We questioned possible association between PJ polyphenolics, macrophage oxidative stress, and cellular PON2 expression, in relation to the activation of specific PON2 transcription factors.

Abetalipoproteinemia in Israel: evidence for a founder mutation in the Ashkenazi Jewish population and a contiguous gene deletion in an Arab patient.

Abetalipoproteinemia (ABL) is a rare autosomal recessive metabolic disorder, characterized by the absence of plasma apolipoprotein B-containing lipoproteins and very low levels of plasma triglycerides and cholesterol. ABL is caused by mutations of the MTP gene. We investigated the genetic basis for ABL in a cohort of Israeli families.

Tissue engineering of vascularized cardiac muscle from human embryonic stem cells.

Transplantation of a tissue-engineered heart muscle represents a novel experimental therapeutic paradigm for myocardial diseases. However, this strategy has been hampered by the lack of sources for human cardiomyocytes and by the scarce vasculature in the ischemic area limiting the engraftment and survival of the transplanted muscle. Beyond the necessity of endothelial capillaries for the delivery of oxygen and nutrients to the grafted muscle tissue, interactions between endothelial and cardiomyocyte cells may also play a key role in promoting cell survival and proliferation.

Coadministration of plasmid DNA constructs encoding an encephalitogenic determinant and IL-10 elicits regulatory T cell-mediated protective immunity in the central nervous system.

We have previously shown that Ag-specific IL-10-producing regulatory T cells (Tr1) participate in the regulation of experimental autoimmune encephalomyelitis and that their specificity undergoes determinant spread in a reciprocal manner to effector T cell specificity. The current study shows that coadministration of plasmid DNA vaccines encoding IL-10 together with a plasmid encoding a myelin basic protein (MBP) encephalitogenic determinant during an ongoing disease rapidly amplifies this Tr1-mediated response, in a disease-specific manner. Thus, coadministration of both plasmids, but not the plasmid DNA encoding MBP alone, rapidly suppresses an ongoing disease.

S-Glutathionylation regulates HDL-associated paraoxonase 1 (PON1) activity.

HDL-associated paraoxonase 1 (PON1) undergoes inactivation under oxidative stress and is preserved by dietary antioxidants. PON1 cysteines can affect PON1 enzymatic activities. S-Glutathionylation, a redox regulatory mechanism characterized by the formation of a mixed disulfide between a protein thiol and oxidized glutathione (GSSG), was shown to preserve some enzymes from irreversible inactivation under pathological conditions.

Myocardial regeneration strategies using human embryonic stem cell-derived cardiomyocytes.

Regenerative medicine is a new biomedicine discipline that takes advantage of the recent advancements in the fields of stem cell biology, molecular biology, and tissue engineering to derive tissue substitutes, in an attempt to replace or modify the function of diseased organs. The heart represents an attractive candidate for these emerging technologies since adult cardiac tissue has limited regenerative capacity. Consequentially, myocardial cell replacement therapy has emerged as a novel therapeutic paradigm for restoration of the myocardial electromechanical function.

A biphasic U-shape effect of cellular oxidative stress on the macrophage anti-oxidant paraoxonase 2 (PON2) enzymatic activity.

Expression of macrophage paraoxonase 2 (PON2), a cellular lactonase with anti-oxidant and anti-atherogenic properties, was shown to be upregulated under high oxidative stress. The aim of the present study was to analyze the relationship between the extent of cellular oxidative stress in J774A.1 macrophage and PON2 lactonase activity under various levels of oxidation, obtained by cell incubation with either anti-oxidants or oxidants.

Local sharing as a predominant determinant of synaptic matrix molecular dynamics.

Recent studies suggest that central nervous system synapses can persist for weeks, months, perhaps lifetimes, yet little is known as to how synapses maintain their structural and functional characteristics for so long. As a step toward a better understanding of synaptic maintenance we examined the loss, redistribution, reincorporation, and replenishment dynamics of Synapsin I and ProSAP2/Shank3, prominent presynaptic and postsynaptic matrix molecules, respectively. Fluorescence recovery after photobleaching and photoactivation experiments revealed that both molecules are continuously lost from, redistributed among, and reincorporated into synaptic structures at time-scales of minutes to hours.

Xenopus laevis POU91 protein, an Oct3/4 homologue, regulates competence transitions from mesoderm to neural cell fates.

Cellular competence is defined as a cell's ability to respond to signaling cues as a function of time. In Xenopus laevis, cellular responsiveness to fibroblast growth factor (FGF) changes during development. At blastula stages, FGF induces mesoderm, but at gastrula stages FGF regulates neuroectoderm formation.

Postprandial serum triacylglycerols and oxidative stress in mice after consumption of fish oil, soy oil or olive oil: possible role for paraoxonase-1 triacylglycerol lipase-like activity.

Objective: Postprandial triacylglycerols and oxidative stress responses are influenced by the type of fat consumed. We investigated the effect of individual unsaturated fatty acids or oils (fish, soy, or olive) on postprandial triglyceridemia response in association with serum resistance to oxidation and paraoxonase-1 (PON1) activity.

Methods: Balb/C mice were supplemented with phosphate buffered saline (control), docosahexaenoic acid (omega-3), linoleic acid (omega-6), or oleic acid (omega-9; 500 microg/300 microL of phosphate buffered saline) and with fish, soy, or olive oil (300 microL); blood samples were collected 2 h after feeding.

Pulmonary hypertension in chronic dialysis patients with arteriovenous fistula: pathogenesis and therapeutic prospective.

Purpose Of Review: End-stage renal disease patients receiving chronic haemodialysis via arteriovenous access often develop various cardiovascular complications, including vascular calcification, cardiac-vascular calcification and atherosclerotic coronary disease. This review describes recently published studies that demonstrate a high incidence of pulmonary hypertension among patients with end-stage renal disease receiving long-term haemodialysis via a surgical arteriovenous fistula. Both end-stage renal disease and long-term haemodialysis via arteriovenous fistula may be involved in the pathogenesis of pulmonary hypertension by affecting pulmonary vascular resistance and cardiac output.

Lysophosphatidylcholine (LPC) attenuates macrophage-mediated oxidation of LDL.

We have previously shown that paraoxonase 1 action on macrophages produced lysophosphatidylcholine (LPC) and significantly decreased cell-mediated LDL oxidation. Thus, in the present study, we questioned whether LPC can directly inhibit macrophage-mediated oxidation of LDL. Addition of increasing LPC concentrations (0-5 microM) to J774A.

Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is an autosomal recessive metabolic disorder characterized by extensive phenotypic and genetic heterogeneity. HFTC was shown recently to result from mutations in two genes: GALNT3, coding for a glycosyltransferase responsible for initiating O-glycosylation, and FGF23, coding for a potent phosphaturic protein. All GALNT3 mutations reported so far have been identified in patients of either Middle Eastern or African-American extraction, corroborating numerous historical reports of the disorder in Africa and in the Middle East.