Methylene blue has intrinsic antimalarial activity and it can act as a chloroquine sensitizer. In addition, methylene blue must be considered for preventing methemoglobinemia, a serious complication of malarial anemia. As an antiparasitic agent, methylene blue is pleiotropic: it interferes with hemoglobin and heme metabolism in digestive organelles, and it is a selective inhibitor of Plasmodium falciparum glutathione reductase. The latter effect results in glutathione depletion which sensitizes the parasite for chloroquine action. At the Centre de Recherche en Santé de Nouna in Burkina Faso, we study the combination of chloroquine with methylene blue (BlueCQ) as a possible medication for malaria in endemic regions. A pilot study with glucose-6-phosphate dehydrogenase-sufficient adult patients has been conducted recently.

The public perception of selenium has changed significantly over the last decades. Originally mainly known for its high toxicity, it was later recognized as an essential trace element and is now (despite its narrow therapeutic window) almost being marketed as a lifestyle drug. Indeed, some clinical and preclinical studies suggest that selenium supplementation may be beneficial in a large number of clinical conditions. However, its mode of action is unresolved in most of these cases. Selenocysteine - identified as the 21st amino acid used in ribosome-mediated protein synthesis - is incorporated in at least 25 specific, genetically determined human selenoproteins, many of which have only recently been discovered. Restoration of normal selenoprotein levels may be - apart from direct supranutritional effects - one possible explanation for the effects of selenium supplements. In this review we provide a brief but up-to-date overview of what is currently known about these 25 acknowledged human selenoproteins and their synthesis.

Methylene blue (MB) has experienced a renaissance mainly as a component of drug combinations against Plasmodium falciparum malaria. Here, we report biochemically relevant pharmacological data on MB such as rate constants for the uncatalyzed reaction of MB at pH 7.4 with cellular reductants like NAD(P)H (k ‫؍‬ 4 M ؊1 s ؊1 ), thioredoxins (k ‫؍‬ 8.5 to 26 M ؊1 s ؊1 ), dihydrolipoamide (k ‫؍‬ 53 M ؊1 s ؊1 ), and slowly reacting glutathione. As the disulfide reductases are prominent targets of MB, optical tests for enzymes reducing MB at the expense of NAD(P)H under aerobic conditions were developed. The product leucomethylene blue (leucoMB) is auto-oxidized back to MB at pH 7 but can be stabilized by enzymes at pH 5.0, which makes this colorless compound an interesting drug candidate. MB was found to be an inhibitor and/or a redox-cycling substrate of mammalian and P. falciparum disulfide reductases, with the k cat values ranging from 0.03 s ؊1 to 10 s ؊1 at 25°C. Kinetic spectroscopy of mutagenized glutathione reductase indicates that MB reduction is conducted by enzyme-bound reduced flavin rather than by the active-site dithiol Cys 58 /Cys 63 . The enzyme-catalyzed reduction of MB and subsequent auto-oxidation of the product leucoMB mean that MB is a redox-cycling agent which produces H 2 O 2 at the expense of O 2 and of NAD(P)H in each cycle, turning the antioxidant disulfide reductases into pro-oxidant enzymes. This explains the terms subversive substrate or turncoat inhibitor for MB. The results are discussed in cellpathological and clinical contexts. Methylene blue (MB or MBϩ ) [also known as methylthionine hydrochloride or 3,7-bis(dimethylamino)phenothiazin-5-ium chloride] was the very first synthetic compound to be used as a drug. Paul Ehrlich, who introduced the concept of modern target-based chemotherapy using MB as an example, and Paul Guttmann described the compound as being an effective antimalarial agent (28). Despite its beneficial antimalarial activity, the drug disappeared from the scene because up-and-coming compounds such as chloroquine were more effective; in addition, soldiers resented taking MB because of inevitable but harmless side effects: green or blue urine and bluish sclerae (47, 55).After MB was revisited as an antimalarial agent (6, 53) and found to be an inhibitor of Plasmodium falciparum glutathione (GSH) reductase (GR) (23), it was studied as a partner drug in antimalarial drug combinations (2,39,48,51).Compared with other antiparasitic agents, MB is affordable and registered in most countries (as the treatment of choice for acute and chronic methemoglobinemia [16,17,36]), and it can be made internationally available in sufficient dosages (51). The price for treating a malaria episode in a child with an MB-containing drug combination would be less than €0.50 (40). Drug resistance has not been reported for MB and could not be provoked in rodent malaria models (52, 53).Because of its favorable properties, including the differential staining of cell biological structures and protein cr...

RAGE is a central driver of tumorigenesis by sustaining an inflammatory tumor microenvironment. This study links the soluble forms of RAGE (sRAGE and esRAGE) with clinical outcome of melanoma patients. Moreover, tissue expression of RAGE was analyzed using immunohistochemistry on two independent tissue microarrays (TMA) containing 35 or 257 primary melanomas, and 41 or 22 benign nevi, respectively. Serum concentrations of sRAGE and esRAGE were measured in 229 Stage III-IV patients using ELISA and plasma concentrations of sRAGE were analyzed in an independent second cohort with 173 samples of Stage I-IV patients. In this cohort, three well-described SNPs in the RAGE gene were analyzed. RAGE protein expression was highly upregulated in primary melanomas compared to benign nevi in the two TMA (p < 0.001 and p 5 0.005) as well as in sun-exposed melanomas (p 5 0.046). sRAGE and esRAGE were identified as prognostic markers for survival as diminished sRAGE (p 5 0.034) and esRAGE (p 5 0.012) serum levels correlated with poor overall survival (OS). Multivariate Cox regression analysis showed that diminished serum sRAGE was independently associated with poor survival (p 5 0.009). Moreover, diminished sRAGE was strongly associated with impaired OS in the second cohort (p < 0.001). Multivariate Cox regression analysis including the investigated SNPs revealed an independent correlation of the two interacting promoter SNPs with impaired OS. In conclusion, the soluble forms of RAGE and variants in its genetic locus are prognostic markers for survival in melanoma patients with high risk for progression.

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As melanoma is an immunogenic tumor, immunotherapy has been investigated as a possible treatment modality for melanoma patients at high risk of relapse and those with metastatic disease. In the past decade progress has been made, ranging from rather nonspecific stimulations of the immune system with IL-2 and IFN-alpha to more specific approaches based on vaccination with tumor antigens. Owing to their unique features, dendritic cells (DCs) represent an important tool for tumor antigen-specific immunotherapy. However, clinical vaccination trials with DCs showed sobering results with respect to objective responses and improvement of overall survival. In this review, principles and methods of DC-based vaccination are presented. Mechanisms impairing clinically successful vaccination strategies are described. Finally, we will discuss perspectives for future developments of DC-based vaccines that might lead melanoma treatment to a new era.

Presumably, there are a high number of unreported cases of allergic diseases in the genital area. Interdisciplinary collaboration between gynecologists, urologists and dermatologist should be increased. The use of methylisothiazolinone in rinse-off and leave-on products should be discussed.