Improvements in health care and lifestyle have led to an elevated lifespan and increased focus on age-associated diseases, such as neurodegeneration, cardiovascular disease, frailty and arteriosclerosis. In all these chronic diseases protein, lipid or nucleic acid modifications are involved, including cross-linked and non-degradable aggregates, such as advanced glycation end products (AGEs). Formation of endogenous or uptake of dietary AGEs can lead to further protein modifications and activation of several inflammatory signaling pathways. This review will give an overview of the most prominent AGE-mediated signaling cascades, AGE receptor interactions, prevention of AGE formation and the impact of AGEs during pathophysiological processes.

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We demonstrated increased 18 F-FDG uptake in injured peripheral nerves in a model of neuropathic pain using small-animal PET/MRI. Methods: A neuropathic pain model in rats was created by spared-nerve injury of the left sciatic nerve. Shamoperated rats without nerve injury were used as a control. The presence of pain was confirmed by testing for allodynia. Sequential small-animal 18 F-FDG PET and MRI scans of the thighs were obtained and coregistered. Autoradiography was performed on harvested nerves and muscle. Results: The group with spared-nerve injury showed the development of allodynia in the operated limb (P , 0.001). Increased 18 F-FDG uptake was observed on both PET/MRI (P , 0.001) and autoradiography (P , 0.005) in the operated nerve in this group. 18 F-FDG uptake in the nerves correlated well with allodynia (r 5 20.59; P , 0.024). Conclusion: Animals with neuropathic pain show increased 18 F-FDG uptake in the affected nerve. Smallanimal PET/MRI can be effectively used to localize 18 F-FDG uptake in peripheral nerves. Increasedspont aneous activity (1) and metabolic changes (2,3) are known to occur in injured nerves and are largely attributed to the symptoms of neuropathic pain. Neuronal activity is dependent on glucose metabolism (4). Isolated cases of increased 18 F-FDG uptake in peripheral nerves have been reported in noncancerous cases of peripheral neuropathy and neural inflammation (5,6). Little is known about glucose metabolism in the peripheral nervous system using 18 F-FDG in the setting of noncancerous nerve injury. To our knowledge, this study was the first systematic study of 18 F-FDG uptake in the peripheral nerves in a noncancerous setting, specifically in a rat model of neuropathic pain. Furthermore, we demonstrated the utility of coregistered MRI in localizing metabolic activity in peripheral nerves. MATERIALS AND METHODS Neuropathic Pain ModelAnimal experiments were approved by the institutional animal care and use committee. Two groups of male adult SpragueDawley rats weighing 200-250 g were used. The first was the spared-nerve injury group (n 5 3), which underwent a left spared-nerve injury procedure that creates a well-characterized neuropathic pain model (7). Briefly, under aseptic surgical techniques and inhalational 2%-3% isoflurane anesthesia, the left sciatic nerve and its 3 terminal branches were surgically accessed. A ligation and axotomy of the tibial and common peroneal nerves was performed, sparing the sural nerve. The second group was a control group (n 5 3), which was subjected to a sham operation similar to that used on the spared-nerve injury animals but without the nerve injury. Animals were permitted to heal for 4 wk after the surgery. Pain Behavior AssessmentAllodynia, a common feature of neuropathic pain, is pain that results from a stimulus that would normally not provoke pain. Development of mechanical allodynia was evaluated during the third week after surgery using von Frey hair filaments. Animals were acclimatized on a raised wire-mesh platform for 2 h/d for 4 d...

The ActA protein of Listeria monocytogenes is an essential virulence factor and is required for intracellular bacterial motility and cell-to-cell spread. plcB, cotranscribed with actA, encodes a broad-specificity phospholipase C that contributes to lysis of host cell vacuoles and cell-to-cell spread. Construction of a transcriptional fusion between actA-plcB and the green fluorescent protein gene of Aequorea victoria has facilitated the detailed examination of patterns of actA/plcB expression within infected tissue culture cells. actA/plcB expression began approximately 30 min postinfection and was dependent upon entry of L. monocytogenes into the host cytosol. L. monocytogenes ⌬hly mutants, which are unable to escape from host cell vacuoles, did not express actA/plcB at detectable levels within infected tissue culture cells; however, complementation of the hly defect allowed entry of the bacteria into the host cytoplasm and subsequent actA/plcB expression. These results emphasize the ability of L. monocytogenes to sense the different host cell compartment environments encountered during the course of infection and to regulate virulence gene expression in response.

The function of many transmembrane molecules can be altered by cleavage and subsequent release of their ectodomains. We have investigated ectodomain cleavage of the cell-cell adhesion and signal-transducing molecule E-cadherin. The E-cadherin ectodomain is constitutively shed from the surface of MCF-7 and MDCKts.srcC12 cells in culture. Release of the 80 kDa soluble E-cadherin fragment is stimulated by phorbol-12-myristate-13-acetate and is inhibited by overexpression of the tissue inhibitor of metalloproteinases-2. The metalloproteinases matrilysin and stromelysin-1 both cleave E-cadherin at the cell surface and release sE-CAD into the medium. The soluble E-cadherin fragment thus released inhibits E-cadherin functions in a paracrine way, as indicated by induction of invasion into collagen type I and inhibition of E-cadherin-dependent cell aggregation. Our results, therefore, suggest a novel mechanism by which metalloproteinases can influence invasion.

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We report here the characterisation of porcine PPARGC1A. Primers based on human PPARGC1A were used to isolate two porcine BAC clones. Porcine coding sequences of PPARGC1A were sequenced together with the splice site regions and the 5′ and 3′ regions. Using direct sequencing nine SNPs were found. Allele frequencies were determined in unrelated animals of five different pig breeds. In the MARC Meishan-White Composite resource population, the polymorphism in exon 9 was significantly associated with leaf fat weight. PPARGC1A has been mapped by FISH to SSC8p21. A (CA)_n microsatellite (SGU0001) has been localised near marker SWR1101 on chromosome 8 by RH mapping and at the same position as marker KS195 (32.5 cM) by linkage mapping. The AseI (nt₈₅₇, Asn/Asn₄₈₉) polymorphism in exon 8 was used to perform linkage analysis in the Hohenheim pedigrees and located the gene in the same genomic region. Transcription of the gene was detected in adipose, muscle, kidney, liver, brain, heart and adrenal gland tissues, which is in agreement with the function of PPARGC1A in adaptive thermogenesis.