Redefine photoprotection: Sun protection beyond sunburn.

Excessive exposure to ultraviolet (UV) light leads to acute and chronic UV damage and is the main risk factor for the development of skin cancer. In most countries with western lifestyle, the topical application of sunscreens on UV-exposed skin areas is by far the most frequently used preventive measure against sunburn. Further than preventing sunburns, increasing numbers of consumers are appreciating sunscreens with a medium- to high-level sun protective factor (SPF) as basis for sustainable-skin ageing or skin cancer prevention programs. However, recent investigations indicate that clinically significant DNA damages as well as a lasting impairment of cutaneous immunosurveillance already occur far below the standard of one minimal erythema dose (MED) sunburn level, which contributes to the current discussion of the clinical value of high-protective SPF values. Ex vivo investigations on human skin showed that the application of SPF30 reduces DNA damage for a day long sun exposure (24 MED) drastically by about 53% but is significantly surpassed by SPF100 reducing DNA damage by approx. 73%. Further analysis on different SPF protection levels in UV-exposed cell culture assays focusing on IL-18, cell vitality and cis/trans-urocanic acid support these findings. Whereas SPF30 and SPF50+ sunscreens already offer a solid UVB cover for most indications, our results indicate that SPF100 provides significant additional protection against mutagenic (non-apoptotic-) DNA damage and functional impairment of the cutaneous immunosurveillance and therefore qualifies as an optimized sunscreen for specifically vulnerable patient groups such as immunosuppressed patients, or skin cancer patients.

Anti-ageing effects of ubiquinone and ubiquinol in a senescence model of human dermal fibroblasts.

Coenzyme Q10 (CoQ10) is an endogenous lipophilic quinone found in equilibrium between its oxidised (ubiquinone) and reduced (ubiquinol) form, ubiquitous in biological membranes and endowed with antioxidant and bioenergetic properties, both crucial to the ageing process. CoQ10 biosynthesis decreases with age in different tissues including skin and its biosynthesis can be modulated by 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors such as statins. Statin-induced CoQ10 deprivation has previously been shown to be associated with the development of a senescence phenotype in cultured human dermal fibroblasts (HDF), hence this model was used to further investigate the role of CoQ10 in skin ageing. The present study aimed to compare the bioavailability of exogenously added CoQ10, in the form of ubiquinone or ubiquinol, to CoQ10-deprived HDF, and to determine their efficacy in rescuing the senescent phenotype induced by CoQ10 deprivation. First, additional senescence markers were implemented to further support the pro-ageing effect of statin-induced CoQ10 deprivation in HDF. Indeed, numerous senescence-associated secretory phenotype (SASP) markers such as p21, IL-8, CXCL1, and MMP-1 were upregulated, whereas components of the extracellular matrix were downregulated (elastin, collagen type 1). Next, we showed that CoQ10 supplementation to statin-treated HDF was able to counteract CoQ10 deprivation and rescued the development of selected senescence/ageing markers in HDF. Ubiquinol resulted more bioavailable than ubiquinone at the same concentration (15 µg/mL) and it significantly improved the cellular oxidative status even within isolated mitochondria highlighting an effective subcellular delivery. Ubiquinol was also more efficient compared to ubiquinone in reverting the expression of the senescent phenotype, quantified in terms of ß-galactosidase positivity, p21, collagen type 1, and elastin at the gene and protein expression levels. In conclusion, our results highlight the pivotal role of CoQ10 for skin vitality and strongly support the use of both forms as a beneficial and effective anti-ageing skin care treatment.

Introduction of principles of blood management to healthy donor bone marrow harvesting.

BACKGROUND AND OBJECTIVES: Patient blood (more accurately: haemoglobin, Hb) management (PBM) aims to optimize endogenous Hb production and to minimize iatrogenic Hb loss while maintaining patient safety and optimal effectiveness of medical interventions. PBM was adopted as policy for patients by the World Health Organization (WHO), and, all the more, should be applied to healthy donors. MATERIALS AND METHODS: Observational data from 489 bone marrow (BM) donors were retrospectively analysed, and principles of patient blood management were applied to healthy volunteer BM donations. RESULTS AND CONCLUSION: We managed to render BM aspiration safe for donors, notably completely avoiding the collection of autologous blood units and blood transfusions through iron management, establishment and curation of high-yield aspiration technique, limitation of collection volume to 1·5% of donor body weight and development of volume prediction algorithms for the requested cell dose.

Inhibition of xanthine oxidase reduces wasting and improves outcome in a rat model of cancer cachexia.

Cachexia is a common co-morbidity in cancer occurring in up to 80% of patients depending on the type of cancer. Uric acid (UA), the end-product of the purine metabolism, is elevated in cachexia due to tissue wasting and upregulated xanthine oxidase (XO) activity. High serum UA levels indicate increased XO-dependent production of oxygen free radicals (reactive oxygen species; ROS) and correlate with metabolic illness and poor survival. We hypothesized that XO-inhibition might reduce inflammatory signals accounting for tissue wasting and improve survival in experimental cancer cachexia. Animals were inoculated intraperitoneally with AH-130 hepatoma cells and treated with two XO-inhibitors: allopurinol [Allo, low (LD) and high dose (HD) 4 and 40 mg/kg/d] and its more effective active metabolite oxypurinol (Oxy, 4 and 40 mg/kg/d) or placebo for 15 days. Weight loss and tissue wasting of both fat and lean tissue (assessed by NMR-scanning) was reduced by both LD and HD Allo and LD-Oxy, but not by HD-Oxy. A robust induction of XO-activity for generation of reactive oxygen species was seen in the placebo group (assessed by electron paramagnetic spectroscopy), which was reduced by XO-inhibition. Increased ROS induced cytokine signaling, proteolytic activity and tissue degradation were all attenuated by XO inhibition. Survival was significantly and dose dependently improved. Food intake and spontaneous locomotor activity were higher, indicating a higher quality of life. Inhibition of XO can reduce tissue wasting and improve survival in cancer cachexia and clearly clinical studies are needed.

The mechanism of assembly and cofactor insertion into Rhodobacter capsulatus xanthine dehydrogenase.

Rhodobacter capsulatus xanthine dehydrogenase (XDH) is a molybdo-flavoprotein that is highly homologous to the homodimeric mammalian xanthine oxidoreductase. However, the bacterial enzyme has an (alphabeta)(2) heterotetrameric structure, and the cofactors were identified to be located on two different polypeptides. We have analyzed the mechanism of cofactor insertion and subunit assembly of R. capsulatus XDH, using engineered subunits with appropriate substitutions in the interfaces. In an (alphabeta) heterodimeric XDH containing the XdhA and XdhB subunits, the molybdenum cofactor (Moco) was shown to be absent, indicating that dimerization of the (alphabeta) subunits has to precede Moco insertion. In an (alphabeta)(2) XDH heterotetramer variant, including only one active Moco-center, the active (alphabeta) site of the chimeric enzyme was shown to be fully active, revealing that the two subunits act independent without cooperativity. Amino acid substitutions at two cysteine residues coordinating FeSI of the two [2Fe-2S] clusters of the enzyme demonstrate that an incomplete assembly of FeSI impairs the formation of the XDH (alphabeta)(2) heterotetramer and, thus, insertion of Moco into the enzyme. The results reveal that the insertion of the different redox centers into R. capsulatus XDH takes place sequentially. Dimerization of two (alphabeta) dimers is necessary for insertion of sulfurated Moco into apo-XDH, the last step of XDH maturation.