Melanocortins and the cholinergic anti-inflammatory pathway.

Experimental evidence indicates that small concentrations of inflammatory molecules produced by damaged tissues activate afferent signals through ascending vagus nerve fibers, that act as the sensory arm of an "inflammatory reflex". The subsequent activation of vagal efferent fibers, which represent the motor arm of the inflammatory reflex, rapidly leads to acetylcholine release in organs of the reticuloendothelial system. Acetylcholine interacts with α7 subunit-containing nicotinic receptors in tissue macrophages and other immune cells and rapidly inhibits the synthesis/release of tumor necrosis factor-α and other inflammatory cytokines. This neural anti-inflammatory response called "cholinergic anti-inflammatory pathway" is fast and integrated through the central nervous system. Preclinical studies are in progress, with the aim to develop therapeutic agents able to activate the cholinergic anti-inflammatory pathway. Melanocortin peptides bearing the adrenocorticotropin/α-melanocyte-stimulating hormone sequences exert a protective and life-saving effect in animals and humans in conditions of circulatory shock. These neuropeptides are likewise protective in other severe hypoxic conditions, such as prolonged respiratory arrest, myocardial ischemia, renal ischemia and ischemic stroke, as well as in experimental heart transplantation. Moreover, experimental evidence indicates that melanocortins reverse circulatory shock, prevent myocardial ischemia/reperfusion damage and exert neuroprotection against ischemic stroke through activation of the cholinergic anti-inflammatory pathway. This action occurs via stimulation of brain melanocortin MC3/MC4 receptors. Investigations that determine the molecular mechanisms of the cholinergic anti-inflammatory pathway activation could help design of superselective activators of this pathway

Update on leukodystrophies and developing trials

Leukodystrophies are a heterogeneous group of rare genetic disorders primarily affecting the white matter of the central nervous system. These conditions can present a diagnostic challenge, requiring a comprehensive approach that combines clinical evaluation, neuroimaging, metabolic testing, and genetic testing. While MRI is the main tool for diagnosis, advances in molecular diagnostics, particularly whole-exome sequencing, have significantly improved the diagnostic yield. Timely and accurate diagnosis is crucial to guide symptomatic treatment and assess eligibility to participate in clinical trials. Despite no specific cure being available for most leukodystrophies, gene therapy is emerging as a potential treatment avenue, rapidly advancing the therapeutic prospects in leukodystrophies. This review will explore diagnostic and therapeutic strategies for leukodystrophies, with particular emphasis on new trials

Adeno-associated viral vector-mediated human vascular endothelial growth factor gene transfer stimulates angiogenesis and wound healing in the genetically diabetic mouse

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Beneficial Effects of Polydeoxyribonucleotide (PDRN) in an In Vitro Model of Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a bilateral, hereditary syndrome characterized by progressive irreversible injury in the corneal endothelium; it is the most frequent cause for corneal transplantation worldwide. Oxidative stress induces the apoptosis of corneal endothelial cells (CECs), and has a crucial function in FECD pathogenesis. The stimulation of the adenosine A2A receptor (A2Ar) inhibits oxidative stress, reduces inflammation and modulates apoptosis. Poly-deoxyribonucleotide (PDRN) is a registered drug that acts through adenosine A2Ar. Thus, the goal of this study was to assess the effect of PDRN in an in vitro FECD model. Human Corneal Endothelial Cells (IHCE) were challenged with H2O2 (200 µM) alone or in combination with PDRN (100 µg/mL), PDRN plus ZM241385 (1 µM) as an A2Ar antagonist, and CGS21680 (1 µM) as a well-known A2Ar agonist. H2O2 reduced the cells’ viability and increased the expression of the pro-inflammatory markers NF-κB, IL-6, IL-1β, and TNF-α; by contrast, it decreased the expression of the anti-inflammatory IL-10. Moreover, the pro-apoptotic genes Bax, Caspase-3 and Caspase-8 were concurrently upregulated with a decrease of Bcl-2 expression. PDRN and CGS21680 reverted the negative effects of H2O2. Co-incubation with ZM241385 abolished the effects of PDRN, indicating that A2Ar is involved in the mode of action of PDRN. These data suggest that PDRN defends IHCE cells against H2O2-induced damage, potentially as a result of its antioxidant, anti-inflammatory and antiapoptotic properties, suggesting that PDRN could be used as an FECD therapy

Candida zemplinina for Production of Wines with Less Alcohol and More Glycerol

We developed a new protocol for winery mixed fermentations, using the selected Candida zemplinina yeaststrain Cz3. The results of a two-year study, in which red musts (Merlot in 2010; Merlot, Nero d’Avolaand Frappato in 2011) were inoculated with Cz3, is discussed. These wines were compared with winesobtained by inoculation with commercial Saccharomyces cerevisiae yeast strains (NDA21 and AR06 in2010; NDA21 in 2011), or with those obtained by spontaneous fermentation (only in 2011). The inoculationof Cz3 always resulted in a two-phase fermentation: the first phase was driven by the C. zemplinina strain,while the second was dominated by the indigenous S. cerevisiae yeasts coming from the grapes and/or thewinery. In both years the Cz3 wines contained less alcohol and more glycerol than those made with thecommercial yeast strains or those obtained by spontaneous fermentation. Triangle tests showed that asensorial difference between wines could only be achieved through the utilisation of Cz3

Genistein supplementation and cardiac function in postmenopausal women with metabolic syndrome: Results from a pilot strain-echo study

Genistein, a soy-derived isoflavone,may improve cardiovascular risk profile in postmenopausal women with metabolic syndrome (MetS), but few literature data on its cardiac effects in humans are available. The aim of this sub-study of a randomized double-blind case-control study was to analyze the effect on cardiac function of one-year genistein dietary supplementation in 22 post-menopausal patients with MetS. Participants received 54 mg/day of genistein (n = 11) or placebo (n = 11) in combination with a Mediterranean-style diet and regular exercise. Left ventricular (LV) systolic function was assessed as the primary endpoint, according to conventional and strain-echocardiography measurements. Also, left atrial (LA) morphofunctional indices were investigated at baseline and at the final visit. Results were expressed as median with interquartile range (IQ). A significant improvement of LV ejection fraction (20.3 (IQ 12.5) vs. -1.67 (IQ 24.8); p = 0.040)), and LA area fractional change (11.1 (IQ 22.6) vs. 2.8 (9.5); p = 0.034)) were observed in genistein patients compared to the controls, following 12 months of treatment. In addition, body surface area indexed LA systolic volume and peak LA longitudinal strain significantly changed from basal to the end of the study in genistein-treated patients. One-year supplementation with 54 mg/day of pure genistein improved both LV ejection fraction and LA remodeling and function in postmenopausal women with MetS

Microguards and micromessengers of the genome

The regulation of gene expression is of fundamental importance to maintain organismal function and integrity and requires a multifaceted and highly ordered sequence of events. The cyclic nature of gene expression is known as ‘transcription dynamics’. Disruption or perturbation of these dynamics can result in significant fitness costs arising from genome instability, accelerated ageing and disease. We review recent research that supports the idea that an important new role for small RNAs, particularly microRNAs (miRNAs), is in protecting the genome against short-term transcriptional fluctuations, in a process we term ‘microguarding’. An additional emerging role for miRNAs is as ‘micromessengers’—through alteration of gene expression in target cells to which they are trafficked within microvesicles. We describe the scant but emerging evidence that miRNAs can be moved between different cells, individuals and even species, to exert biologically significant responses. With these two new roles, miRNAs have the potential to protect against deleterious gene expression variation from perturbation and to themselves perturb the expression of genes in target cells. These interactions between cells will frequently be subject to conflicts of interest when they occur between unrelated cells that lack a coincidence of fitness interests. Hence, there is the potential for miRNAs to represent both a means to resolve conflicts of interest, as well as instigate them. We conclude by exploring this conflict hypothesis, by describing some of the initial evidence consistent with it and proposing new ideas for future research into this exciting topic

Preventing Prostate Biopsy Complications: to Augment or to Swab?

Aims for Improvement The aim of this study was to determine the antibiotic prophylaxis associated with the fewest infectious complications following prostate biopsy Determining the safest method allows the Jefferson Department of Urology to modify its biopsy protocol and improve the rate of post-biopsy complication

TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation

Despite its importance during viral or bacterial infections, transcriptional regulation of the interferon-β gene (Ifnb1) in activated macrophages is only partially understood. Here we report that TRIM33 deficiency results in high, sustained expression of Ifnb1 at late stages of toll-like receptor-mediated activation in macrophages but not in fibroblasts. In macrophages, TRIM33 is recruited by PU.1 to a conserved region, the Ifnb1 Control Element (ICE), located 15 kb upstream of the Ifnb1 transcription start site. ICE constitutively interacts with Ifnb1 through a TRIM33-independent chromatin loop. At late phases of lipopolysaccharide activation of macrophages, TRIM33 is bound to ICE, regulates Ifnb1 enhanceosome loading, controls Ifnb1 chromatin structure and represses Ifnb1 gene transcription by preventing recruitment of CBP/p300. These results characterize a previously unknown mechanism of macrophage-specific regulation of Ifnb1 transcription whereby TRIM33 is critical for Ifnb1 gene transcription shutdown

Soy protein supplementation does not cause lymphocytopenia in postmenopausal women

BACKGROUND: The health benefits of soy isoflavones have been widely investigated; however, there are some concerns as to whether soy isoflavones, similar to ipriflavone, a synthetic isoflavone, cause lymphocytopenia in postmenopausal women. Hence, the purpose of this study was to investigate the extent to which 12-month supplementation of 25 g soy protein containing 60 mg isoflavones alters lymphocyte counts or other hematological parameters in postmenopausal women who were not on hormone replacement therapy. METHODS: Eighty-seven postmenopausal women were randomly assigned to receive either soy protein or an equivalent amount of control protein devoid of isoflavones. Fasting venous blood was collected at baseline and at the end of twelve month study period for complete blood count analyses. RESULTS: Between the two treatment groups, the percent changes in hematological parameters, including lymphocytes, were not different. While women consuming the soy supplement had an increase in mean corpuscular hemoglobin concentration (MCHC) and red cell distribution width index (RDW; a marker of reticulocytes), women consuming the control diet had higher percentage of only MCHC. CONCLUSION: Overall, the results of the present study indicate that consumption of 25 g soy protein containing 60 mg isoflavones daily for one year does not cause lymphocytopenia