Tuesday, July 24, 2012

Indexed abstracts (on going list)


Vascul Pharmacol. 2012 Sep-Oct;57(2-4):91-7. doi: 10.1016/j.vph.2012.05.003. Epub 2012 May 15.
From excess adiposity to insulin resistance: the role of free fatty acids.
University of Foggia, Department of Internal Medicine and Geriatrics, Foggia, Italy. a.capurso@alice.it
With a positive caloric balance, adipocytes undergo excessive hypertrophy, which causes adipocyte dysfunction, as well as adipose tissue endocrine and immune responses. A preferential site of fat accumulation is the abdominal-perivisceral region, due to peculiar factors of the adipose tissue in such sites, namely an excess of glucocorticoid activity, which promotes the accumulation of fat; and the greater metabolic activity and sensitivity to lipolysis, due to increased number and activity of β3-adrenoceptors and, partly, to reduced activity of α2-adrenoceptors. As a consequence, more free fatty acids (FFA) are released into the portal system. Hypertrophic adipocytes begin to secrete low levels of TNF-α, which stimulate preadipocytes and endothelial cells to produce MCP-1, in turn responsible for attracting macrophages to the adipose tissue, thus developing a state of chronic low-grade inflammation which is causally linked to insulin resistance. Excess of circulating FFA, TNF-α and other factors induces insulin resistance. FFA cause insulin resistance by inhibiting insulin signaling through the activation of serin-kinases, i.e. protein kinase C-Θ, and the kinases JNK and IKK, which promote a mechanism of serine phosphorylation of Insulin Receptor Substrates (IRS), leading to interruption of the downstream insulin receptor (IR) signaling. TNF-α, secreted by hypertrophic adipocytes and adipose tissue macrophages, also inhibits IR signaling by a double mechanism of serine-phosphorylation and tyrosine-dephosphorylation of IRS-1, causing inactivation and degradation of IRS-1 and a consequent stop of IR signaling. Such mechanisms explain the transition from excess adiposity to insulin resistance, key to the further development of type 2 diabetes.
Copyright © 2012 Elsevier Inc. All rights reserved.
PMID: 22609131


Pediatrics. 2012 Mar;129(3):557-70. doi: 10.1542/peds.2011-2912. Epub 2012 Feb 20.
Toward a unifying hypothesis of metabolic syndrome.
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Despite a lack of consistent diagnostic criteria, the metabolic syndrome (MetS) is increasingly evident in children and adolescents, portending a tsunami of chronic disease and mortality as this generation ages. The diagnostic criteria for MetS apply absolute cutoffs to continuous variables and fail to take into account aging, pubertal changes, and race/ethnicity. We attempt to define MetS mechanistically to determine its specific etiologies and to identify targets for therapy. Whereas the majority of studies document a relationship of visceral fat to insulin resistance, ectopic liver fat correlates better with dysfunctional insulin dynamics from which the rest of MetS derives. In contrast to the systemic metabolism of glucose, the liver is the primary metabolic clearinghouse for 4 specific foodstuffs that have been associated with the development of MetS: trans-fats, branched-chain amino acids, ethanol, and fructose. These 4 substrates (1) are not insulin regulated and (2) deliver metabolic intermediates to hepatic mitochondria without an appropriate "pop-off" mechanism for excess substrate, enhancing lipogenesis and ectopic adipose storage. Excessive fatty acid derivatives interfere with hepatic insulin signal transduction. Reactive oxygen species accumulate, which cannot be quenched by adjacent peroxisomes; these reactive oxygen species reach the endoplasmic reticulum, leading to a compensatory process termed the "unfolded protein response," driving further insulin resistance and eventually insulin deficiency. No obvious drug target exists in this pathway; thus, the only rational therapeutic approaches remain (1) altering hepatic substrate availability (dietary modification), (2) reducing hepatic substrate flux (high fiber), or (3) increasing mitochondrial efficiency (exercise).
PMID: 22351884 


Nature. 2005 Feb 17;433(7027):760-4.
Rejuvenation of aged progenitor cells by exposure to a young systemic environment.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
The decline of tissue regenerative potential is a hallmark of ageing and may be due to age-related changes in tissue-specific stem cells. A decline in skeletal muscle stem cell (satellite cell) activity due to a loss of Notch signalling results in impaired regeneration of aged muscle. The decline in hepatic progenitor cell proliferation owing to the formation of a complex involving cEBP-alpha and the chromatin remodelling factor brahma (Brm) inhibits the regenerative capacity of aged liver. To examine the influence of systemic factors on aged progenitor cells from these tissues, we established parabiotic pairings (that is, a shared circulatory system) between young and old mice (heterochronic parabioses), exposing old mice to factors present in young serum. Notably, heterochronic parabiosis restored the activation of Notch signalling as well as the proliferation and regenerative capacity of aged satellite cells. The exposure of satellite cells from old mice to young serum enhanced the expression of the Notch ligand (Delta), increased Notch activation, and enhanced proliferation in vitro. Furthermore, heterochronic parabiosis increased aged hepatocyte proliferation and restored the cEBP-alpha complex to levels seen in young animals. These results suggest that the age-related decline of progenitor cell activity can be modulated by systemic factors that change with age.
PMID: 15716955


Genes Dev. 2007 Dec 15;21(24):3244-57. Epub 2007 Nov 30.
Motif module map reveals enforcement of aging by continual NF-kappaB activity.
Program in Epithelial Biology and Cancer Biology Program, Stanford University School of Medicine, Stanford, California 94305, USA.
Aging is characterized by specific alterations in gene expression, but their underlying mechanisms and functional consequences are not well understood. Here we develop a systematic approach to identify combinatorial cis-regulatory motifs that drive age-dependent gene expression across different tissues and organisms. Integrated analysis of 365 microarrays spanning nine tissue types predicted fourteen motifs as major regulators of age-dependent gene expression in human and mouse. The motif most strongly associated with aging was that of the transcription factor NF-kappaB. Inducible genetic blockade of NF-kappaB for 2 wk in the epidermis of chronologically aged mice reverted the tissue characteristics and global gene expression programs to those of young mice. Age-specific NF-kappaB blockade and orthogonal cell cycle interventions revealed that NF-kappaB controls cell cycle exit and gene expression signature of aging in parallel but not sequential pathways. These results identify a conserved network of regulatory pathways underlying mammalian aging and show that NF-kappaB is continually required to enforce many features of aging in a tissue-specific manner.
PMID: 18055696 


Crit Care Med. 1988 Mar;16(3):246-51.
Glucagon antagonism of calcium channel blocker-induced myocardial dysfunction.
Department of Anesthesiology and Child Health and Development, George Washington University School of Medicine, Washington, DC.
Calcium channel blockers (CCBs) may produce profound myocardial depression. Glucagon antagonized verapamil-induced hypotension and bradycardia in rats; however, glucagon's ability to antagonize other CCBs is unexplored. This study determined: a) if glucagon reverses verapamil-induced depression by a direct cardiac effect, b) if myocardial depression induced by diltiazem and nifedipine (representing different classes of CCBs) is also reversed by glucagon, and c) the glucagon concentration needed to reverse myocardial depression. Isolated rat hearts were perfused at a constant flow rate in a Langendorff preparation. Developed pressure (dP), contractility (+dP/dtmax), relaxation (-dP/dtmax), heart rate, and coronary vascular resistance were recorded. A CCB (n = 6, each blocker) was infused until greater than 50% depression of contractility was achieved. Glucagon was then simultaneously infused (perfusion concentration of 0.6-1.1 x 10(-7) M), and repeat cardiac variables were recorded. In a separate group of 36 hearts, glucagon dose response was determined. After producing a greater than 50% depression in dP/dtmax with 3 mumol of diltiazem, a single concentration of glucagon was infused simultaneously into each heart (perfusion concentrations between 10(-6) and 10(-9) M) and percent recovery of baseline function was determined. Glucagon restored baseline contractility and dP with all three CCBs. Complete reversal of diltiazem-induced myocardial depression occurs at glucagon concentrations greater than or equal to 5 x 10(-7) M. We conclude that a) glucagon directly reverses myocardial depression from three classes of CCBs at concentrations achieved in vivo, and b) glucagon may be useful in the treatment of CCB-induced myocardial toxicity.
PMID: 3277781


C R Seances Soc Biol Fil. 1996;190(2-3):243-53.
[Calcium signal and contraction].
[Article in French]
INSERM Unité 99, Hôpital Henri-Mondor, Créteil, France.
The calcium ion plays a unique role as a messenger and a cofactor in cardiac contraction. This role relies on the strict control by the cell of Ca homeostasis, the components of which are described in this review. During the few last years, tools for the measurement of free intracellular Ca in living cells have been developed which include: probes (aequorin, Fura 2, Indo 1, Fluo 3...), tools for the loading of the cells (microinjection and AM-probes) and systems to analyze the signal (photometers, microfluorimeters, confocal microscopy). Those tools allowed the analysis of calcium signal in cardiomyocytes. In the cardiac cell, activation of a Ca influx through L type Ca channels is usually considered as the pathway initializing Ca mobilization and leading to contraction. It has now been demonstrated that this pathway is activated by beta 1-adrenergic agonists via cyclic AMP. However, amplification of contraction may involve other targets. Thus, the positive inotropic effect of beta 2-adrenergic agonists is also associated with a rise in cytosolic Ca but is not linked to cyclic AMP increase. The alpha 1-adrenergic pathway involves a sensitization of myofilaments for Ca, and increases contraction without an increase in cytosolic Ca. Finally, the positive inotropic effect of glucagon combines the cyclic AMP pathway with a cyclic AMP independent pathway triggered by the metabolite mini-glucagon.
PMID: 8869235


 2007 Jan;292(1):G395-401. Epub 2006 Oct 19.

Adenosine inhibits cytosolic calcium signals and chemotaxis in hepatic stellate cells.


Section of Digestive Diseases, Yale Univ., 333 Cedar St., 1080 LMP, PO Box 208019, New Haven, CT 06520-8019, USA.


Adenosine is produced during cellular hypoxia and apoptosis, resulting in elevated tissue levels at sites of injury. Adenosine is also known to regulate a number of cellular responses to injury, but its role in hepatic stellate cell (HSC) biology and liver fibrosis is poorly understood. We tested the effect of adenosine on the cytosolic Ca2+ concentration, chemotaxis, and upregulation of activation markers in HSCs. We showed thatadenosine did not induce an increase in the cytosolic Ca2+ concentration in LX-2 cells and, in addition, inhibited increases in the cytosolic Ca2+ concentration in response to ATP and PDGF. Using a Transwell system, we showed that adenosine strongly inhibited PDGF-induced HSCchemotaxis in a dose-dependent manner. This inhibition was mediated via the A(2a) receptor, was reversible, was reproduced by forskolin, and was blocked by the adenylate cyclase inhibitor 2,5-dideoxyadenosine. Adenosine also upregulated the production of TGF-beta and collagen I mRNA. In conclusion, adenosine reversibly inhibits Ca2+ fluxes and chemotaxis of HSCs and upregulates TGF-beta and collagen I mRNA. We propose thatadenosine provides 1) a "stop" signal to HSCs when they reach sites of tissue injury with high adenosine concentrations and 2) stimulates transdifferentiation of HSCs by upregulating collagen and TGF-beta production.