A reappraisal of the biological functions of melanins and melanogens: The role of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) in skin (photo)protection

Solar ultraviolet rays (UVR) play an important role in melanoma and non-melanoma skin cancer development while melanins, produced by melanocytes, are involved in photoprotection, control of oxidative stress, regulation of skin homeostasis and immunity. The ratio between the two main groups of melanin, eumelanins and pheomelanins, is regulated by the mc1r gene encoding for melanocortin-1-receptor (MC1R), whose inactivation causes a switch from eumelanin to pheomelanin production. While eumelanins are considered to be photoprotective, pheomelanins are known to be (photo)toxic as they lead to the production of reactive oxygen species in the presence and in the absence of UV radiation. It seems that not only eumelanins but even their precursors can contribute to the (photo)protective action. In particular, 5,6-dihydroxyindole-2-carboxylic acid (DHICA) and its main metabolite 6-hydroxy-5- methoxyindole-2-carboxylic acid (6H5MICA) have antioxidant properties so they could play a critical role in the responses of the melanocyte to oxidative stress and inflammation. Moreover, it has been showed that DHICA is able to act as a chemical messenger inducing antioxidant defense systems and cell differentiation in keratinocytes. On these basis, DHICA and its methylated metabolite could play an important role in chemopreventive strategies of melanoma skin cancer

Efficacy of ginger as antiemetic in children with acute gastroenteritis: a randomised controlled trial

Background: Ginger is a spice with a long history of use as a traditional remedy for nausea and vomiting. No data on the efficacy of ginger are presently available for children with vomiting associated with acute gastroenteritis (AGE). Aim: To test whether ginger can reduce vomiting in children with AGE. Methods: Double-blind, randomised placebo-controlled trial in outpatients aged 1 to 10 years with AGE-associated vomiting randomised to ginger or placebo. The primary outcome was the occurrence of ≥1 episode of vomiting after the first dose of treatment. Severity of vomiting and safety were also assessed. Results: Seventy-five children were randomised to the ginger arm and 75 to the placebo arm. Five children in the ginger arm and 4 in the placebo arm refused to participate in the study shortly after randomisation, leaving 70 children in the ginger arm and 71 in the placebo arm (N = 141). At intention-to-treat analysis (N = 150), assuming that all children lost to follow-up had reached the primary outcome, the incidence of the main outcome was 67% (95% CI 56 to 77) in the ginger group and 87% (95% CI 79 to 94) in the placebo group, corresponding to the absolute risk reduction for the ginger versus the placebo group of −20% (95% CI −33% to −7%, P = 0.003), with a number needed to treat of 5 (95% CI 3 to 15). Conclusion: Oral administration of ginger is effective and safe at improving vomiting in children with AGE. Trial registration: The trial was registered on https://clinicaltrials.gov/ with the identifier NCT02701491

Human red hair pheomelanin is a potent pro-oxidant mediating Uv- independent mechanisms of oxidative stress in red hair phenotypes

Traditionally, the positive correlation between red hair and melanoma has been attributed to both the poor antioxidant and photoprotective properties of pheomelanins compared to the dark eumelanins, and the capacity of pheomelanin to act as photosensitizer inducing generation of reactive oxygen species upon UV irradiation. Recently, the occurrence of UV-independent pathways of carcinogenesis was provided by a series of experiments showing that induction of an activating mutation of BRAF into red mice resulted in a high incidence of invasive melanomas in the absence of UV stimulation . In addition, the skin of pheomelanic mice contained higher levels of oxidative DNA and lipid damage with respect to albino-Mc1re/e mice (Mitra et al, Nature 2012, 491, 449-453). These data clearly showed that the pheomelanin pathway could mediate oxidative stress and melanomagenesis ; however the mechanisms have not so far addressed at molecular level. To get an insight into these processes we investigated the reactivity of pheomelanin pigment isolated from human red hair (RHP) and synthetic pheomelanins from cysteinyldopa (CD-Mel) toward critical cellular antioxidants such as GSH and NAD(P)H. Data showed a remarkable increase in the oxidation rate of both compounds in the presence of RHP compared to the controls, whereas much less marked variations were noticed with the eumelanin extracted from black hair. HPLC analysis consistently indicated a rise in GSH disulfide (GSSG) levels with GSH decrease, confirming a redox reaction. Formation of NAD(P)+ was similarly observed in the reaction mixture of NAD(P)H with RHP. In the absence of oxygen, GSH and NAD(P)H depletion was not observed while the presence of enzymes as superoxide dismutase and catalase did not modify the effect of pheomelanin suggesting a ROS independent mechanism. Similar effects were obtained with CD-Mel confirming that the prooxidant effects are due to the pheomelanic component. The mechanism of GSH oxidation by RHP was investigated by EPR spectroscopy. Besides inducing antioxidant depletion, RHP, like CD-Mel, proved also capable of promoting autoxidation of melanin precursors, such as 5-S-cysteinyldopa and dopa, under conditions of exclusion of light, with formation of pheomelanin or eumelanin pigments. This effect is oxidative in character, since it depends on oxygen, revealing a remarkable prooxidant capacity of the pigment serving as a biocatalyst for non-enzymatic melanogenesis (Panzella et al., PCMR 2014, 27,244-252; Greco et al. Chem Comm. 2011,47, 10308-10310). A mechanism has been proposed to account for the observed effects in which GSH, NAD(P)H and melanin precursors oxidation is not mediated by ROS, but is the result of a direct redox exchange with oxidized 1,4-benzothiazine units within the pigment scaffold. Re-oxidation of reduced pheomelanin by oxygen with formation of ROS would ensure shuttling of pheomelanin between the redox states. Overall these results provide a unifying chemical framework into which to explain the mechanisms underlying the relationships between pheomelanin pigmentation and oxidative stress

Transperineal Laser Ablation (TPLA) Treatment of Focal Low–Intermediate Risk Prostate Cancer

background: this interventional pilot study aimed to evaluate the short-term (3 years) efficacy of focal laser ablation (FLA) in treating the index lesion of low–intermediate-risk prostate cancer, along with assessing the safety of the procedure (ClinicalTrials.gov ID NCT04045756). methods: forty patients aged between 46 and 86 with histologically proven organ-confined prostate cancer and low-to-intermediate progression risk were included. FLA was performed under percutaneous fusion magnetic resonance/ultrasound guidance in a day hospital setting under local anesthesia. patients underwent regular clinical and functional assessments through the international index of erectile function (IIEF-5) and the International prostatism symptom score (IPSS), PSA measurements, post-procedure MRI scans, and biopsies at 36 months or if positive findings were detected earlier. statistical analyses were conducted to assess trends in PSA levels and cavity dimensions over time. results: forty patients were initially included, with fifteen lost to follow-up. At 36 months, a mean PSA reduction of 60% was observed, and 80% of MRI scans showed no signs of in-field clinically significant residual/recurrent cancer. biopsies at 36 months revealed no malignant findings in 20 patients. no deterioration in sexual function or urinary symptoms was recorded. conclusions: FLA appears to be safe, feasible, and effective in the index lesion treatment of low–intermediate-risk prostate cancer, with a high rate of tumor eradication and preservation of quality of life

Preventive Effect of Cow's Milk Fermented with Lactobacillus paracasei CBA L74 on Common Infectious Diseases in Children: A Multicenter Randomized Controlled Trial

Background: Fermented foods have been proposed to prevent common infectious diseases (CIDs) in children attending day care or preschool

Coenzyme Q10 supplementation reduces peripheral oxidative stress and inflammation in interferon-β1a-treated multiple sclerosis

Background: Oxidative stress is a driver of multiple sclerosis (MS) pathology. We evaluated the effect of coenzyme Q10 (CoQ10) on laboratory markers of oxidative stress and inflammation, and on MS clinical severity. Methods: We included 60 relapsing–remitting patients with MS treated with interferon beta1a 44μg (IFN-β1a) with CoQ10 for 3 months, and with IFN-β1a 44μg alone for 3 more months (in an open-label crossover design). At baseline and at the 3 and 6-month visits, we measured markers of scavenging activity, oxidative damage and inflammation in the peripheral blood, and collected data on disease severity. Results: After 3 months, CoQ10 supplementation was associated with improved scavenging activity (as mediated by uric acid), reduced intracellular reactive oxygen species production, reduced oxidative DNA damage, and a shift towards a more anti-inflammatory milieu in the peripheral blood [with higher interleukin (IL)-4 and IL-13, and lower eotaxin, granulocyte-macrophage colony-stimulating factor (GM-CSF), hepatocyte growth factor (HGF), interferon (IFN)-γ, IL-1α, IL-2R, IL-9, IL-17F, macrophage inflammatory proteins (MIP)-1α, regulated on activation-normal T cell expressed and secreted (RANTES), tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF). Also, CoQ10 supplementation was associated with lower Expanded Disability Status Scale, fatigue severity scale, Beck’s depression inventory, and the visual analogue scale for pain. Conclusions: CoQ10 supplementation improved scavenging activity, reduced oxidative damage, and induced a shift towards a more anti-inflammatory milieu, in the peripheral blood of relapsing–remitting MS patients treated with 44μg IFN-β1a 44μg. A possible clinical effect was noted but deserves to be confirmed over longer follow ups

Intrecci di motivi e temi nel Medioevo germanico e romanzo

The impulse to bring together scholars of Germanic philology and Romance philology to discuss the interlacing of motifs and themes in both traditions derives from the awareness of the many and varying ties between the two fields. Linguistic, literary, philological and textual relationships are common grounds for the two disciplines, but, surprisingly, they have often been neglected by the research. The papers selected by the editors and included in this interdisciplinary miscellany bring to light both constants and variants between the Germanic and the Romance traditions, outlining an even wider and deeper network of cultural connections than previously thought

Automatic and Dynamic Composition of Web Services Using Ontologies

Ontology-driven Web Services composition represents a novel approach to provide value added services or to improve services availability. Here we describe how ontology can be exploited to express the composition criteria, which can be automatically processed to obtain different workflows with the same semantic. Each workflow can be used to generate an orchestrated or a chorographical execution plan, whose actor contributes to provide the final service. We present a simple implementation as proof of concept using an OWL description of the composition criteria and the JENA APIs to process it

Automatic and Dynamic Composition of Web Services Using Ontologies

Ontology-driven Web Services composition represents a novel approach to provide value added services or to improve services availability. Here we describe how ontology can be exploited to express the composition criteria, which can be automatically processed to obtain different workflows with the same semantic. Each workflow can be used to generate an orchestrated or a chorographical execution plan, whose actor contributes to provide the final service. We present a simple implementation as proof of concept using an OWL description of the composition criteria and the JENA APIs to process it