Inflammation and skin cholesterol in LDLr−/−, apoA-I−/− mice: link between cholesterol homeostasis and self-tolerance?

Diet-fed low density lipoprotein receptor-deficient/apolipoprotein A-I-deficient (LDLr-/-, apoA-I-/-) mice accumulate a 10-fold greater mass of cholesterol in their skin despite a 1.5- to 2-fold lower plasma cholesterol concentration compared with diet-fed LDLr-/- mice. The accumulation of cholesterol predominantly in the skin has been shown to occur in a growing number of other hypercholesterolemic double knockout mouse models sharing deficits in genes regulating cellular cholesterol homeostasis. Exploring the relationship between cholesterol balance and inflammation, we have examined the time course of cholesterol accumulation in a number of extrahepatic tissues and correlated with the onset of inflammation in diet-fed LDLr-/-, apoA-I-/- mice. After 4 weeks of diet, LDLr-/-, apoA-I-/- mice showed a significant increase in skin cholesterol mass compared with LDLr-/- mice. In addition, after 4 weeks on the diet, cholesterol accumulation in the skin was also found to be associated with macrophage infiltration and accompanied by increases in tumor necrosis factor-alpha, cyclooxygenase-2, and langerin mRNA, which were not seen in the liver. Overall, these data suggest that as early as 4 weeks after starting the diet, the accumulation of skin cholesterol and the onset of inflammation occur concurrently. In summary, the use of hypercholesterolemic LDLr-/-, apoA-I-/- mice may provide a useful tool to investigate the role that apoA-I plays in maintaining cholesterol homeostasis and its relationship to inflammation.     

Altered complexin expression in psychiatric and neurological disorders: cause or consequence?

Complexins play a critical role in the control of fast synchronous neurotransmitter release. They operate by binding to trimeric SNARE complexes consisting of the vesicle protein Synaptobrevin and the plasma membrane proteins Syntaxin and SNAP-25, which are key executors of membrane fusion reactions. SNARE complex binding by Complexins is thought to stabilize and clamp the SNARE complex in a highly fusogenic state, thereby providing a pool of readily releasable synaptic vesicles that can be released quickly and synchronously in response to an action potential and the concomitant increase in intra-synaptic Ca(2+) levels. Genetic elimination of Complexins from mammalian neurons causes a strong reduction in evoked neurotransmitter release, and altered Complexin expression levels with consequent deficits in synaptic transmission were suggested to contribute to the etiology or pathogenesis of schizophrenia, Huntington's disease, depression, bipolar disorder, Parkinson's disease, Alzheimer's disease, traumatic brain injury, Wernicke's encephalopathy, and fetal alcohol syndrome. In the present review I provide a summary of available data on the role of altered Complexin expression in brain diseases. On aggregate, the available information indicates that altered Complexin expression levels are unlikely to have a causal role in the etiology of the disorders that they have been implicated in, but that they may contribute to the corresponding symptoms.     

Mitochondrial dysfunction: A potential link between neuroinflammation and neurodegeneration?

Dysfunctional mitochondria are thought to play a cardinal role in the pathogenesis of various neurological disorders, such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and stroke. In addition, neuroinflammation is a common denominator of these diseases. Both mitochondrial dysfunction and neuroinflammatory processes lead to increased production of reactive oxygen species (ROS) which are detrimental to neurons. Therefore, neuroinflammation is increasingly recognized to contribute to processes underlying neurodegeneration. Here we describe the involvement of mitochondrial (dys)function in various neurological disorders and discuss the putative link between mitochondrial function and neuroinflammation.     

Myzostomida: a link between trochozoans and flatworms?

Myzostomids are obligate symbiotic invertebrates associated with echinoderms with a fossil record that extends to the Ordovician period. Due to their long history as host-specific symbionts, myzostomids have acquired a unique anatomy that obscures their phylogenetic affinities to other metazoans: they are incompletely segmented, parenchymous, acoelomate organisms with chaetae and a trochophore larva. Today, they are most often classified within annelids either as an aberrant family of polychaetes or as a separate class. We inferred the phylogenetic position of the Myzostomida by analysing the DNA sequences of two slowly evolving nuclear genes: the small subunit ribosomal RNA and elongation factor-1alpha. All our analyses congruently indicated that myzostomids are not annelids but suggested instead that they are more closely related to flatworms than to any trochozoan taxon. These results, together with recent analyses of the myzostomidan ultrastructure, have significant implications for understanding the evolution of metazoan body plans, as major characters (segmentation, coeloms, chaetae and trochophore larvae) might have been independently lost or gained in different animal phyla.     

AMPK: a link between metabolism and reproduction?

5'AMP-activated protein kinase (AMPK) is a serine/threonine kinase that acts as a fuel gauge in regulating energy metabolism. It restores cellular ATP levels by switching on catabolic pathways and switching off anabolic pathways. Some evidence indicates that AMPK could be also implicated in reproductive functions such as granulosa cell steroidogenesis and nuclear oocyte maturation in several species. Some metabolic hormones such as leptin, resistin, adiponectin (three adipokines) and ghrelin may in part act through the AMPK signaling. These hormones are also involved in the control of the reproductive functions at the hypothalamus-pituitary-gonadal axis level in both male and female. Thus, AMPK could be one of the signaling pathways controlling the interactions between energy balance and reproduction. The reproductive system is tightly coupled with energy balance, and thereby metabolic abnormalities can lead to the development of some physiopathological situations such as the polycystic ovary syndrome (PCOS). Women with PCOS show altered fertility mostly associated with metabolic disorders such as insulin-resistance, hyperinsulinemia and/or dyslipidemia. Metformin, an insulin-sensitizer, is used for the treatment of women with PCOS. It restores subnormal fertility and energy balance. Recent studies show that AMPK is involved in the mechanism of action of metformin. Thus, it may be a therapeutic target. However, further investigations are necessary to elucidate the functions of AMPK in both metabolic and reproductive tissues.     

Presenilins: A novel link between intracellular calcium signaling and lysosomal function?

Mutations in presenilins (PS), transmembrane proteins encoding the catalytic subunit of γ-secretase, result in familial Alzheimer's disease (FAD). Several studies have identified lysosomal defects in cells lacking PS or expressing FAD-associated PS mutations, which have been previously attributed to a function for PS in lysosomal acidification. Now, in this issue, Coen et al. (2012. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201201076) provide a series of results that challenge this idea and propose instead that presenilins play a role in calcium-mediated lysosomal fusion.     

A mechanistic link between chick diet and decline in seabirds?

A climatic regime shift during the mid-1970s in the North Pacific resulted in decreased availability of lipid-rich fish to seabirds and was followed by a dramatic decline in number of kittiwakes breeding on the Pribilof Islands. Although production of chicks in the mid-1970s was adequate to sustain kittiwake populations in the early 1980s, the disappearance of birds from breeding colonies apparently exceeded recruitment. No mechanism has been proposed to explain why recruitment would differ among fledglings fed lipid-rich or lipid-poor fish during development. Here we show that diets low in lipids induce nutritional stress and impair cognitive abilities in young red-legged kittiwakes, Rissa brevirostris. Specifically, growth retardation, increased secretion of stress hormones and inferior ability to associate food distribution with visual cues were observed in individuals fed lipid-poor diets. We conclude that lipid-poor diets during development affect the quality of young seabirds, which is likely to result in their increased mortality and low recruitment.     

iPLA2β and its role in male fertility,neurological disorders,metabolic disorders,and inflammation

The Ca²⁺-independent phospholipases, designated as group VI iPLA₂s, also referred to as PNPLAs due to their shared homology with patatin, include the β, γ, δ, ε, ζ, and η forms of the enzyme. The iPLA₂s are ubiquitously expressed, share a consensus GXSXG catalytic motif, and exhibit organelle/cell-specific localization. Among the iPLA₂s, iPLA₂β has received wide attention as it is recognized to be involved in membrane remodeling, cell proliferation, cell death, and signal transduction. Ongoing studies implicate participation of iPLA₂β in a variety of disease processes including cancer, cardiovascular abnormalities, glaucoma, and peridonditis. This review will focus on iPLA₂β and its links to male fertility, neurological disorders, metabolic disorders, and inflammation.     

Is the endogenous digitalis-like factor the link between hypertension and metabolic disorders as diabetes mellitus, obesity and acromegaly?

Endogenous factors cross-reacting with antidigoxin antibodies have been found in several tissues and body fluids of animals and humans, using commercially available digoxin radioimmunoassay or enzyme immunoassay methods. The chemical characteristics of these endogenous factors are, at present, unknown, although it has been suggested that they could be substances with low molecular weight. Experimental studies and theoretical considerations indicate that endogenous digitalis-like factors (DDLFs), in addition to the ability to react with antibodies, might also bind to the specific cellular receptor of the cardiac glycosides and thus inhibit the membrane Na+/K(+)-ATPase (sodium pump). Therefore, EDLF can be an endogenous modulator of the membrane sodium-potassium pump and several authors have suggested that EDLF could play a role in the regulation of fluids and electrolytes, muscular tone of myocardial and also in the pathogenesis of arterial hypertension. In this review, the authors discuss the hypothesis that, in metabolic diseases such as diabetes mellitus, obesity and acromegaly, the sodium retention and volume expansion, possibly due to exaggerated sodium intake, and/or exogenously induced peripheral hyperinsulinemia and high levels of growth hormone, could trigger a sustained release of EDLF, which in turn increases the blood pressure.     

The human mandible: Lever,link, or both?

Hylander ('78) recently published important new data on bite force in humans, and showed that the human mandible cannot function purely as a link during incisal biting. He concluded instead that the mandible acts as a lever. Reexamination of Hylander's data suggests that the mandible cannot function purely as a lever either, and in fact it probably functions simultaneously as both lever and link during incisal biting.     

Antidiabetic pharmacology: a link between metabolic syndrome and neuro-oncology?

One of the main topics of the annual meeting of the American Society for Clinical Oncology in 2011 were the results presented on breast cancer chemotherapy and concomitant administration of the oral antidiabetic metformin. The overall agreement was that current evidence is just enough to dramatically change the clinical practice of oncology, and in our case, brain cancer treatment, and that further research is needed to address the relationship between diabetes, metabolism, insulin analogues and neoplasia. Still, it is very interesting to explore the potentially beneficial effects of metformin in glioma chemo/immunotherapy and wait for results in the clinic. In the current paper we present the cell and molecular aspects of the metabolic syndrome, metformin administration and cancer chemotherapy, with a special emphasis in neuro-oncology, since brain tumors are usually devastating diseases with an extremely high mortality within two years of diagnosis even when surgical, radiotherapeutic and chemotherapeutic interventions are applied.