Assessing the frequency of adverse reactions induced by melanin-containing formulations used for the management of solar dermatitis.

BACKGROUND: Melanin from different sources is widely used by many manufacturers to produce cosmetics and sunscreens. Research data show a wide spectrum of biological activities of melanin including the protection against UV radiation and oxidants. According to the research evidence, the topical use of melanin is more effective against inflammation than the hydrocortisone. The most common side effects of topical melanin ointment are local itching, burning, and moderate hyperemia. AIM OF THE STUDY: The purpose of this work is to describe the adverse outcomes of melanin-containing formulas in patients with solar dermatitis, and to compare the frequency of adverse reactions with data from different research reports. METHODS: A Pharmacovigilance questionnaire was developed to assess potential adverse events attributable to the use of melanin ointment. We used a modified survey tool created by Jaber and coauthors. This survey of melanin application documents validated reports of adverse events manifested by objective skin changes. MEDLINE (Ovid); MEDLINE In-Process Citations & Daily Update (Ovid); PubMed (NLM) (Internet); Embase (Ovid); and Cochrane Database of Systematic Reviews were searched for the evidence on adverse reactions of topical melanin application. RESULTS: The responses documented in this survey show reliability and safety of melanin formula used for the photoprotection and treatment of solar dermatitis. Most symptoms encountered in those using melanin were consistent with exposure to excessive amount (more than 4 times per day) of the compound applied topically. Of the total 534 survey responses received, 74% reported no adverse events. A total of 140 completed adverse event reports. Melanin ointment was being administered for the indications of photo injury (burns) in 75%, photodermatitis in 18%, and solar eczematous dermatitis in 7% of patients. Data were compared with rates from other reports. CONCLUSION: We have no evidence that the chemical structure of melanin varies with currently available products, used locally or in other countries, nor that any such variability played any role in the events reported here. Further studies are required to compare the adverse events of topical melanin formulas containing melanins of different origin.

Orally administered melanin from Sepiapharaonis ink ameliorates depression-anxiety-like behaviors in DSS-induced colitis by mediating inflammation pathway and regulating apoptosis.

The effects of intestinal inflammation on the brain and behavior have received a lot of attention. Melanin (MSI) from Sepiapharaonis ink as an emerging functional food, it exhibited a significant protective effect on dextran sulfate sodium (DSS) induced colitis in previous study. In present study, C57BL/6J mice were free to drink 2.5% DSS solution to establish the colitis model. During the DSS treatment, mice were orally administrated with MSI once per day (75, 150, and 300 mg/kg, respectively). The results showed that MSI treatment ameliorated the depression and anxiety symptoms of colitis mice. Further mechanism studies indicated that MSI alleviated inflammatory response by adjusting cytokines TNF-α, IL-1ß, IFN-γ, and IL-10, and proteins NLRP3/ASC/caspase-1 inflammasome), inhibited the activation of microglia, restored brain synaptic density, reduced oxidative stress (SOD, MDA) and regulated apoptosis (tunel staining, caspase-3). MSI could modulate depression-anxiety states by targeting inflammation, nerve tissue, oxidative stress and apoptosis. MSI administration could serve as an emerging blue food and nutrition strategy for the prevention of digestive tract inflammation and behavioral disorders.

Anti-Melanogenesis Effects of Lotus Seedpod In Vitro and In Vivo.

Melanogenesis has many important physiological functions. However, abnormal melanin production causes various pigmentation disorders. Melanin synthesis is stimulated by α-melanocyte stimulating hormone (α-MSH) and ultraviolet (UV) irradiation. Lotus seedpod extract (LSE) has been reported as possessing antioxidative, anti-aging, and anticancer activities. The present study examined the effect of LSE on melanogenesis and the involved signaling pathways in vitro and in vivo. Results showed that non-cytotoxic doses of LSE and its main component epigallocatechin (EGC) reduced both tyrosinase activity and melanin production in the α-MSH-induced melanoma cells. Western blotting data revealed that LSE and EGC inhibited expressions of tyrosinase and tyrosinase-related protein 1 (TRP-1). Phosphorylation of p38 and protein kinase A (PKA) stimulated by α-MSH was efficiently blocked by LSE treatment. Furthermore, LSE suppressed the nuclear level of cAMP-response element binding protein (CREB) and disturbed the activation of melanocyte inducing transcription factor (MITF) in the α-MSH-stimulated B16F0 cells. The in vivo study revealed that LSE inhibited melanin production in the ear skin of C57BL/6 mice after exposure to UVB. These findings suggested that the anti-melanogenesis of LSE involved both PKA and p38 signaling pathways. LSE is a potent novo natural depigmenting agent for cosmetics or pharmaceutical applications.

Fungal melanins that deteriorate paper cultural heritage: An overview.

Paper-based works of art and documents of cultural importance kept in museums and libraries can show notorious signs of deterioration, including foxing stains, caused by fungal colonization. Some of the main chromophore agents of fungal origin that deteriorate paper and therefore affect paper cultural heritage both aesthetically and structurally are the group of pigments called melanins. Thus, knowledge of the diversity and features of fungal melanins and of the melanization pathways of fungi growing on paper is key to removing these pigments from paper-based works of cultural importance. This review provides an approach about the current knowledge of melanins synthesized by paper-colonizing fungi, their localization in the fungal structures, and their role in the deterioration of paper. This knowledge might contribute to developing new, effective, and sustainable strategies of restoration and conservation of historical documents and works of art based on paper.

A first-in-human study of the novel metabolism-based anti-cancer agent SM-88 in subjects with advanced metastatic cancer.

Purpose SM-88 (D,L-alpha-metyrosine; racemetyrosine) is a novel anti-cancer agent, used with melanin, phenytoin, and sirolimus (SMK Therapy). This pilot first-in-human study characterized the safety, tolerability, and efficacy of SMK Therapy in subjects with advanced metastatic cancer. Methods All subjects (n = 30) received SMK Therapy for an initial 6 week Cycle (5 days on, 2 off per week) and continued if well tolerated. Safety signals, clinical response, overall survival, progression free survival (PFS), and quality of life changes were assessed. Results The most common drug related adverse events were hyperpigmentation and rash. All drug related adverse events were mild to moderate in intensity. Following treatment with SMK Therapy, 4 subjects achieved complete response, 6 partial response, and 17 stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (total clinical benefit 90%). Responses were observed within 6 weeks, and continued to improve, with 3 complete and 3 partial responders achieving best response after at least 3.2 months. Durable stable disease was observed, lasting a median duration of 11 months (range 1-31 months). Median overall survival for all subjects was 29.8 months, and median PFS was 13 months. Following 6 weeks of treatment, most (83.3%) subjects showed an improvement in Eastern Cooperative Oncology Group (ECOG) score and an improvement in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ 30) global health status (baseline 61.2 ± 25.0; end of Cycle 1 80.7 ± 14.7; n = 29; p < 0.001). Conclusions The results of this study support continued development of SM-88.

A standardized method based on pigmented epidermal models evaluates sensitivity against UV-irradiation.

To protect the human skin from extensive solar radiation, melanocytes produce melanin and disperse it via melanosomes to keratinocytes in the basal and suprabasal layers of the human epidermis. Moreover, melanocytes are associated with pathological skin conditions such as vitiligo and psoriasis. Thus, an in vitro skin model that comprises a defined cutaneous pigmentation system is highly relevant in cosmetic, pharmaceutical and medical research. Here, we describe how the epidermal-melanin-unit can be established in vitro. Therefore, primary human melanocytes are implemented in an open source reconstructed epidermis. Following 14 days at the air liquid interface, a differentiated epidermis was formed and melanocytes were located in the basal layer. The functionality of the epidermal-melanin-unit could be shown by the transfer of melanin to the surrounding keratinocytes, and a significantly increased melanin content of models stimulated with either UV-radiation or the melanin precursor dihydroxyphenylalanine. Additionally, an UV50 assay was developed to test the protective effect of melanin. In analogy to the IC50 value in risk assessment, the UV50 value facilitates a quantitative investigation of harmful effects of natural UV-radiation to the skin in vitro. Employing this test, we could demonstrate that the melanin content correlates with the resilience against simulated sunlight, which comprises 2.5 % UVB and 97.5 % UVA. Besides demonstrating the protective effect of melanin in vitro, the assay was used to determine the protective effect of a consumer product in a highly standardized setup.

Inhibition of complement alternative pathway suppresses experimental autoimmune anterior uveitis by modulating T cell responses.

The objective of the current study was to delineate the pathway of complement activation that is crucial for the induction of experimental autoimmune anterior uveitis (EAAU). We studied the development of EAAU in melanin-associated antigen (MAA)-sensitized Lewis rats treated with antibody against C4 or factor B. Control animals received isotype IgG control. Antibody against C4 had no effect on EAAU, and all of the animals developed EAAU similar to those injected with control IgG. In contrast, EAAU was completely inhibited in all MAA-sensitized Lewis rats injected with factor B antibody. Treatment with anti-factor B antibody resulted in suppression of ocular complement activation. Adoptive transfer of T lymphocytes harvested from draining lymph nodes of donor animals treated with anti-factor B did not transfer EAAU to naïve syngenic rats. Anti-factor B antibody inhibited the ability of MAA-specific CD4(+) T cells to proliferate (in vitro) in response to MAA in a dose-dependent manner. Level of TNF-α and IFN-γ decreased in the presence of anti-factor B. Collectively, our results provide the novel finding that complement activation via the alternative pathway contributes to intraocular inflammation in EAAU, and anti-factor B-mediated inhibition of EAAU is due to diminished antigen-specific CD4(+) T cell responses to MAA. Our findings explain the interactions between the complement system and T cells that are critical for the induction of EAAU and may lead to the development of therapy for idiopathic anterior uveitis based on selective blockade of the alternative pathway.

Interaction of neomycin, tobramycin and amikacin with melanin in vitro in relation to aminoglycosides-induced ototoxicity.

The aim of this study was to examine in vitro the interaction between aminoglycoside antibiotics displaying adverse ototoxic effects and melanin which is a constituent of the inner ear. The binding of neomycin, tobramycin and amikacin to model synthetic melanin was studied. It has been demonstrated that all the investigated aminoglycosides form stable complexes with melanin biopolymer. The obtained results show that the amount of drug bound to melanin increases with the increase of initial drug concentration and the incubation time. An analysis of drugs binding to melanin by the use of Scatchard plots has shown that at least two classes of independent binding sites must be implicated in the studied aminoglycoside antibiotic-melanin complexes formation: strong binding sites (n1) with the association constant K1 approximately 0.2-2.0 x 10(5) M(-1) and weak binding sites (n2) with K2 approximately 1.0-4.9 x 10(3) M(-1). Based on the values of association constants the following order of drugs affinity to DOPA-melanin was found: tobramycin > amikacin >> neomycin. The ability of the analyzed aminoglycoside antibiotics to form complexes with melanin in vitro may be one of the reasons for their ototoxicity in vivo, as a result of their accumulation in melanin in the inner ear.

Melanoniquia inducida por zidovudina / No disponible

No disponible

Chronic intracerebroventricular infusion of MCH causes obesity in mice. Melanin-concentrating hormone.

Melanin-concentrating hormone (MCH) is a cyclic amino acid neuropeptide localized in the lateral hypothalamus. Although MCH is thought to be an important regulator of feeding behavior, the involvement of this peptide in body weight control has been unclear. To examine the role of MCH in the development of obesity, we assessed the effect of chronic intracerebroventricular infusion of MCH in C57BL/6J mice that were fed with regular or moderately high-fat (MHF) diets. Intracerebroventricular infusion of MCH (10 microg/day for 14 days) caused a slight but significant increase in body weight in mice maintained on the regular diet. In the MHF diet-fed mice, MCH more clearly increased the body weight accompanied by a sustained hyperphagia and significant increase in fat and liver weights. Plasma glucose, insulin, and leptin levels were also increased in the MCH-treated mice fed the MHF diet. These results suggest that chronic stimulation of the brain MCH system causes obesity in mice and imply that MCH may have a major role in energy homeostasis.

Efecto de la cloroquina en la uveítis experimental recurrente inducida con melanina bovina en ratas Lewis / Effect of chloroquine on experimental melanin-protein induced uveitis in Lewis rats

Objetivo: Valorar la efectividad de la cloroquina para el control de la UER.Material y Métodos: Se indujo uveítis con melanina bovina en 8 ratas y a 6 de éstas se les administró cloroquina a 5 mg/kg/día durante 6 meses. Se aplicaron dos reinyecciones de melanina para inducir recurrencias. Las ratas se sacrificaron cuando presentaron uveítis después del segundo refuerzo y se estudiaron histopatológicamente. A un grupo adicional de 4 ratas se les administró cloroquina para valorar su toxicidad en retina.Resultados: las dos ratas que no recibieron cloroquina tuvieron 3 cuadros de uveítis severa a diferencia del grupo de cloroquina que presentó 3 cuadros de uveítis leve a moderada clínica e histopatológicamente. p < 0.05 El grupo de ratas sin uveítis tratada con cloroquina no mostró alteraciones clínicas ni histopatológicas.Conclusiones: la cloroquina fue capaz de disminuir la duración y la intensidad de la uveítis e incluso pudo inhibir la aparición de nuevos cuadros, por lo que consideramos es un fármaco útil para el tratamiento de la UER.

Binding of drugs to eye melanin is not predictive of ocular toxicity.

Ocular melanin is found in the uveal tract and in the pigmented epithelial layer of the retina. Many structurally and pharmacologically unrelated drugs from different therapeutic classes bind to melanin. Examples include numerous drugs acting on the central nervous system, beta-blockers, beta-agonists, antimalarial drugs, sympathomimetic amines, and antibiotics. The critical factors are the acid/base status and the lipophilicity of the molecule. In all cases, there are no direct consequences of drug-melanin binding. Drug-related toxic effects on the retina described in humans and animals are unrelated to melanin binding: melanin binding and retinal toxicity are two separate entities, the latter being related to the intrinsic toxicity of the compound rather than its ability to bind. Chloroquine and phenothiazines are often used as examples of drugs with retinal toxicity linked to melanin binding. In both cases however, experimental data show that the toxic mechanism is unrelated to binding. Melanin binding has also been found to be protective against the ocular toxicity of some drugs. In conclusion, we believe that potential ocular toxicity of future drugs can be assessed adequately by conducting well-designed toxicology studies, and using nonpigmented rodents in addition to pigmented nonrodent species remains fully justified. Binding of drugs to eye melanin is not predictive of ocular toxicity.

Induction of experimental autoimmune anterior uveitis by a self-antigen: melanin complex without adjuvant.

PURPOSE: Experimental autoimmune anterior uveitis (EAAU) is an organ-specific autoimmune disease induced by immunization with bovine melanin-associated antigen (MAA) and two adjuvants (complete Freund's adjuvant and purified pertussis toxin). This study was undertaken to explore whether an adjuvant is required in the induction of EAAU. METHODS: Insoluble MAA was extracted from the bovine iris and ciliary body. Soluble bovine MAA was derived by treatment of insoluble MAA with the proteolytic enzyme, V8 protease. Lewis rats were immunized with the insoluble or soluble antigen, with or without adjuvant (complete Freund's adjuvant and purified pertussis toxin). Adoptive transfer of CD4+ and CD8+ T cells was performed to investigate the pathogenesis of EAAU. RESULTS: Experimental autoimmune anterior uveitis can be induced in Lewis rats by immunization with 100 g insoluble bovine MAA alone without the use of adjuvants. The disease can be adoptively transferred to naive syngenic rats by primed CD4+ T cells. In contrast, soluble bovine MAA was not uveitogenic unless adjuvants were employed. CONCLUSIONS: The data suggest that EAAU can be induced in the Lewis rat without addition of an adjuvant. Future studies concerning the pathogenesis of EAAU can now be performed without the possible confounding effect of an adjuvant.

A paramagnetic agent causing ochronotic arthropathy.

Magnetic resonance imaging (MRI) identified a paramagnetic substance in the hyaline cartilage of the hips and knees in a patient with ochronosis. Chemical studies characterized the paramagnetic agent as melanin. The free radicals contained in melanin were shown to initiate cytotoxicity. The loss of cartilage in ochronotic arthropathy now can be explained at the electron level using the superoxide theory of oxygen toxicity. Inappropriate metabolism of oxygen also may explain early cartilage degeneration in hemochromatosis, hemosiderosis, and Wilson's disease.

Mutagenicity of melanin from human red hair.

The Salmonella typhimurium histidine reversion test of Ames et al. was used to demonstrate the pheomelanin, the red-brown polymeric pigment produced in human skin and hair, becomes mutagenic after exposure to long wave-length UV-light; a finding consistent with the UV-induced somatic mutation hypothesis for the origin of freckles and the high susceptibility of redheads and blonds to sunlight-induced skin cancers.