The translocator protein (peripheral benzodiazepine receptor) mediates rat-selective activation of the mitochondrial permeability transition by norbormide

We have investigated the mechanism of rat-selective induction of the mitochondrial permeability transition (PT) by norbormide (NRB). We show that the inducing effect of NRB on the PT (i) is inhibited by the selective ligands of the 18kDa outer membrane (OMM) translocator protein (TSPO, formerly peripheral benzodiazepine receptor) protoporphyrin IX, N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide and 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one; and (ii) is lost in digitonin mitoplasts, which lack an intact OMM. In mitoplasts the PT can still be induced by the NRB cationic derivative OL14, which contrary to NRB is also effective in intact mitochondria from mouse and guinea pig. We conclude that selective NRB transport into rat mitochondria occurs via TSPO in the OMM, which allows its translocation to PT-regulating sites in the inner membrane. Thus, species-specificity of NRB toward the rat PT depends on subtle differences in the structure of TSPO or of TSPO-associated proteins affecting its substrate specificity.     

A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories

Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example, the expression of an aversive behaviour upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinction are only beginning to emerge. Here, we show that fear extinction initiates upregulation of hippocampal insulin-growth factor 2 (Igf2) and downregulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation, we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2 signalling during fear extinction. To this end, we show that fear extinction-induced IGF2/IGFBP7 signalling promotes the survival of 17-19-day-old newborn hippocampal neurons. In conclusion, our data suggest that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory.     

Quinolone/fluoroquinolone susceptibility in Escherichia coli correlates with human polymicrobial bacteriuria and with in vitro interleukine-8 suppression

Urinary tract infections (UTIs) are frequently polymicrobial diseases mainly sustained by Escherichia coli in association with other opportunistic pathogens. Cystitis and pyelonephritis are usually accompanied by an inflammatory response, which includes neutrophil recruitment. Uropathogenic E. coli possess the ability to evade host defenses, modulating the innate immune response. The aim of this study was to determine whether particular E. coli strains correlate with polymicrobial bacteriuria and whether escape from the early host defenses and microbial synergy could lead to mixed UTIs. We evaluated 188 E. coli-positive urine samples and assessed the relationships among polymicrobism, neutrophil presence and several traits of E. coli isolates (virulence factors such as hlyA, fimA, papC and their relative products, i.e. hemolysin, type 1 and P fimbriae, and cnf1, their phylogenetic group) and their ability to suppress cytokine response in 5637 bladder epithelial cells. Escherichia coli susceptibility toward quinolones and fluoroquinolones, known to be linked to the pathogenicity of this species, was also considered. We found significant correlations among polymicrobial bacteriuria, absence of pyuria and quinolone/fluoroquinolone susceptibility of E. coli isolates and their enhanced capability to suppress interleukin-8 urothelial production when compared with the patterns induced by the resistant strains.     

Potential therapeutic applications of mesenchymal stem cells for the treatment of eye diseases

Stem cell-based treatments have been extensively explored in the last few decades to develop therapeutic strategies aimed at providing effective alternatives for those human pathologies in which surgical or pharmacological therapies produce limited effects. Among stem cells of different sources, mesenchymal stem cells (MSCs) offer several advantages, such as the absence of ethical concerns, easy harvesting, low immunogenicity and reduced tumorigenesis risks. Other than a multipotent differentiation ability, MSCs can release extracellular vesicles conveying proteins, mRNA and microRNA. Thanks to these properties, new therapeutic approaches have been designed for the treatment of various pathologies, including ocular diseases. In this review, the use of different MSCs and different administration strategies are described for the treatment of diabetic retinopathy, glaucoma, and retinitis pigmentosa. In a large number of investigations, positive results have been obtained by in vitro experiments and by MSC administration in animal models. Most authors agree that beneficial effects are likely related to MSC paracrine activity. Based on these considerations, many clinical trials have already been carried out. Overall, although some adverse effects have been described, promising outcomes are reported. It can be assumed that in the near future, safer and more effective protocols will be developed for more numerous clinical applications to improve the quality of life of patients affected by eye diseases.     

The ability of the mitochondrial Ca2+-binding glycoprotein to restore Ca2+ transport in glycoprotein-depleted rat liver mitochondria

Rat liver mitochondria may be subfractionated in sediment and supernatant fractions by swelling in the presence of EDTA and oxaloacetate. The sediment is largely depleted of the Ca²⁺-binding glycoprotein and its Ca²⁺-transporting activity may be as low as 10–20% of the starting value. Both the rate of Ca²⁺ uptake and the capacity to maintain a high Ca²⁺ concentration gradient across the membrane are depressed. Addition of an osmotic supernatant to the assay mixture may partially restore the original Ca²⁺-transporting ability. The active component in the supernatant is the Ca²⁺-binding glycoprotein. This is shown by the following facts: (a) the effect is enhanced by the addition of the purified glycoprotein to the supernatant; (b) precipitation of the glycoprotein from the supernatant by affinity chromatography-purified antibodies abolishes the stimulatory effect, and (c) in the presence of 130 μM Mg²⁺, the glycoprotein alone may restore fully the Ca²⁺-transporting ability of the particles. The maximal velocity is already reached at 0.1 μg glycoprotein/mg mitochondrial protein.     

Change in protective coloration in the striated shieldbug <Emphasis Type=Italic>Graphosoma lineatum</Emphasis> (Heteroptera: Pentatomidae): predator avoidance and generalization among different life stages

There are two major forms of protective coloration, camouflage and warning coloration, which often entail different colour pattern characteristics. Some species change strategy between or within life stages and one such example is the striated shieldbug, Graphosoma lineatum. The larvae and the pale brownish-and-black striated pre-diapause adults are more cryptic in the late summer environment than is the red-and black striation that the adults change to after diapause in spring. Here we investigate if the more cryptic pre-diapause adult and larval coloration may affect the aposematic function of the coloration as compared to the red adult form. In a series of trials we presented fifth instar larvae, pale or red adults to shieldbug-naïve domestic chicks, Gallus gallus domesticus, to investigate the birds’ initial wariness, avoidance learning, and generalization between the three prey types. The naïve chicks found the red adults most aversive followed by pale adults, and they found the larvae the least aversive. The birds did not find the larvae unpalatable and did not learn to avoid them, while they learned to avoid the two adult forms and then to a similar degree. Birds generalized asymmetrically between life stages, positively from larvae to adults and negatively from adults to larvae. We conclude that the lower conspicuousness in the pale forms of G. lineatum may entail a reduced aposematic function, namely a reduced initial wariness in inexperienced birds. The maintenance of the colour polymorphism is discussed.     

New insights into the ecology and biology of Acanthocheilonema reconditum (Grassi, 1889) causing canine subcutaneous filariosis

In spite of its wide distribution among dogs and the evidence of its implication as a zoonotic agent, scant information is available on the biology of Acanthocheilonema reconditum (Spirurida, Onchocercidae). In this study, blood samples from 152 Sicilian dogs were examined for A. reconditum microfilariae at the beginning of the study and 1 year later. The periodicity of microfilaraemia was investigated by bleeding 2 highly microfilaraemic dogs twice a day for 10 days and, later on, every 2 weeks for 1 year and a third animal every 3 h for 96 h. Fleas and ticks infesting dogs were collected and dissected for the detection of A. reconditum larvae. The prevalence of infestation was 11·2% (17/152) and 13·3% (16/120) at the beginning and at the end of the study, with a 1 year cumulative incidence of 5·9%. Although dogs bled twice a day showed a higher number of microfilariae in most of the morning samples, the absence of any circadian rhythm was suggested by data of the third experiment conducted by bleeding a dog every 3 h for 4 days. A. reconditum developing forms were detected in 5·1% (4/78) of dissected fleas, but not in any of the 272 ticks. The study provides new insights into the biology and ecology of this dog filarioid in its definitive and intermediate hosts.     

Multiple tumor marker elevation in androgen ablation-refractory prostate cancer with long-term response to metronomic chemotherapy: a case report

Outcomes in hormone-refractory prostate cancer are very poor. The time from progression to death is only 12-19 months. We present the case of a 69-year-old man with hormone-refractory prostate cancer and bone metastases treated with metronomic chemotherapy (cyclophosphamide based). He had had a colon adenocarcinoma ten years before. The atypical features of this case were an unusually long-lasting response to metronomic chemotherapy and an increase in serum levels of some non-prostate-specific tumor markers (CEA and CA 19-9) that was not related to a relapse of colon cancer. We hypothesize a potential role of hypoxia inducing CA 19-9 and CEA expression in tumor cells, which may predict the development of progressive resistance to antiangiogenic therapies.