Pigmentary Effects Research Articles

Antifibrotic and Anti-Inflammatory Actions of α-Melanocytic Hormone: New Roles for an Old Player.

The melanocortin system encompasses melanocortin peptides, five receptors, and two endogenous antagonists. Besides pigmentary effects generated by α-Melanocytic Hormone (α-MSH), new physiologic roles in sexual activity, exocrine secretion, energy homeostasis, as well as immunomodulatory actions, exerted by melanocortins, have been described recently. Among the most common and burdensome consequences of chronic inflammation is the development of fibrosis. Depending on the regenerative capacity of the affected tissue and the quality of the inflammatory response, the outcome is not always perfect, with the development of some fibrosis. Despite the heterogeneous etiology and clinical presentations, fibrosis in many pathological states follows the same path of activation or migration of fibroblasts, and the differentiation of fibroblasts to myofibroblasts, which produce collagen and α-SMA in fibrosing tissue. The melanocortin agonists might have favorable effects on the trajectories leading from tissue injury to inflammation, from inflammation to fibrosis, and from fibrosis to organ dysfunction. In this review we briefly summarized the data on structure, receptor signaling, and anti-inflammatory and anti-fibrotic properties of α-MSH and proposed that α-MSH analogues might be promising future therapeutic candidates for inflammatory and fibrotic diseases, regarding their favorable safety profile.

Elastin structure and its involvement in skin photoageing

Skin aging is a complex process that may be caused by factors that are intrinsic and extrinsic to the body. Ultraviolet (UV) radiation represents one of the main sources of skin damage over the years and characterizes a process known as photoaging. Among the changes that affect cutaneous tissue with age, the loss of elastic properties caused by changes in elastin production, increased degradation and/or processing produces a substantial impact on tissue esthetics and health. The occurrence of solar elastosis is one of the main markers of cutaneous photoaging and is characterized by disorganized and non-functional deposition of elastic fibers. The occurrence of UV radiation-induced alternative splicing of the elastin gene, which leads to inadequate synthesis of the proteins required for the correct assembly of elastic fibers, is a potential explanation for this phenomenon. Innovative studies have been fundamental for the elucidation of rarely explored photoaging mechanisms and have enabled the identification of effective therapeutic alternatives such as cosmetic products. This review addresses cutaneous photoaging and the changes that affect elastin in this process.

Comparison of pigmentary side effects of taxanes and anthracyclines: an onychoscopic evaluation

Background: Taxanes and anthracyclines are considered as fundamental drugs for the treatment of a broad range of cancers. They have several side effects, which may limit their usage. Drug-induced nail pigmentation (DHNP) has been reported as one of the most striking dermatological side effect of both taxanes and doxorubicin.Objective: This study aimed to evaluate and compare pigmentary side effects of taxanes and doxorubicin with the help of onychoscopy.Methods: Forty-one consecutive patients (30 women, 11 men) with a diagnosis of cancer (16 gastric cancer, 25 breast cancer) were prospectively enrolled in a period of six months. Patients were categorized according to the chemotherapy regimens they had been administered: docetaxel received group [docetaxel (60 mg/m2, day 1), cisplatin (60 mg/m2, day 1) and fluorouracil (500 mg/m2, days 1–5) every 3 weeks], paclitaxel received group [paclitaxel (80–175 mg/m2) every 21 days with or without trastuzumab/zoledronic acid] and doxorubicin received group [doxorubicin 50–60 mg/m2 and cyclophosphamide 600–750 mg/m2 every 21 days]. All the patients were asked whether they had diabetes mellitus (DM) and peripheral neuropathy. At the 16 weeks of chemotherapy, for each patient, all fingernails and toenails were evaluated in clinical and dermoscopic examinations for nail pigmentation. Dermoscopic examination was performed using a videodermatoscope. Descriptive statistics were computed for means, standard deviations, and frequencies. Chi-square test or Fisher’s exact tests were used for the statistical analysis, with a significance threshold of p < 0.05.Results: 34.1% of the patients (14/41) demonstrated clinical signs of nail pigmentation. Nail pigmentation was observed in 4 of 13 patients (30.8%), who had received doxorubicin; 10 of 28 patients (35.7%), who had received taxanes (docetaxel and paclitaxel). There was no statistically significant relationship between the nail pigmentation and the type of the chemotherapeutic regimen administered (Fisher’s exact test, p = 1.000). In addition, no statistically significant results were observed between nail pigmentation and DM (Fisher’s exact test, p = 0.393), and nail pigmentation and peripheral neuropathy (Fisher’s exact test, p = 1.000).Conclusions: DHNP may cause considerable distress to patients. Dermoscopy is a noninvasive imaging method that increases diagnostic accuracy of both pigmented and nonpigmented lesions. Typical dermoscopic features of DHNP consist of a homogeneous brownish-gray coloration of the background with thin, longitudinal, gray lines, which allow the examiner to clearly make the correct diagnosis. Further studies are needed to assess both clinical and dermoscopical findings of DHNP.

Spectrally tuned structural and pigmentary coloration of birdwing butterfly wing scales.

The colourful wing patterns of butterflies play an important role for enhancing fitness; for instance, by providing camouflage, for interspecific mate recognition, or for aposematic display. Closely related butterfly species can have dramatically different wing patterns. The phenomenon is assumed to be caused by ecological processes with changing conditions, e.g. in the environment, and also by sexual selection. Here, we investigate the birdwing butterflies, Ornithoptera, the largest butterflies of the world, together forming a small genus in the butterfly family Papilionidae. The wings of these butterflies are marked by strongly coloured patches. The colours are caused by specially structured wing scales, which act as a chirped multilayer reflector, but the scales also contain papiliochrome pigments, which act as a spectral filter. The combined structural and pigmentary effects tune the coloration of the wing scales. The tuned colours are presumably important for mate recognition and signalling. By applying electron microscopy, (micro-)spectrophotometry and scatterometry we found that the various mechanisms of scale coloration of the different birdwing species strongly correlate with the taxonomical distribution of Ornithoptera species.

Melanocortin 1 receptor and skin pathophysiology: beyond colour, much more than meets the eye

The melanocortin 1 receptor (MC1R), a G protein-coupled receptor preferentially expressed in melanocytes, mediates the pigmentary effects of α melanocyte-stimulating hormone (αMSH). MC1R is also expressed in other cutaneous cell types, particularly keratinocytes and dermal fibroblasts, suggesting non-pigmentary actions of the αMSH/MC1R system. Böhm and Stegemann now report a dramatic effect of mouse Mc1r functional status on susceptibility to skin fibrosis and collagen types I and III metabolism, in a study combining the powerful mouse model provided by the natural Mc1r(e/e) knockout and an established model of skin fibrosis. The study underscores the antifibrotic role for the skin αMSH/MC1R system.

Does erythropoietin modulate human hair follicle melanocyte activities in situ?

Erythropoietin (EPO) is now appreciated for not only drive erythopoiesis, but also to exert additional functions. Since we had previously shown that human hair follicles (HFs) are both an extra-renal source and an extra-medullary target of EPO, we have now studied whether one such function is the regulation of HF pigmentation. Human anagen VI HFs were treated with EPO (100 IU/ml) in serum-free organ culture. Unexpectedly, we noticed greatly divergent pigmentary effects of EPO, since both up- and down-regulation of HF melanin content and tyrosinase activity in situ was seen in HF derived from different individuals. These divergent effects could not be attributed to differences in skin regions, the total HF melanocyte number or specific traits of individual HF donors. Our pilot study provides first evidence suggesting that EPO may modulate normal human melanocyte functions under physiologically relevant conditions in situ.

β‐Defensin 3: a novel and unexpected key that unlocks the melanocortin 1 receptor

β‐Defensin 3: a novel and unexpected key that unlocks the melanocortin 1 receptor

Plenty New Under the Sun

Variation at the melanocortin 1 receptor (MC1R) is very common in most non-African world populations. A range of variants predispose to skin cancer, including melanoma. What remains unclear are the mechanisms linking gene variation with sun sensitivity or tumor risk. In particular, it remains unclear whether pigmentary effects of the MC1R can account for all of the increase in cancer risk.

Serpentine supravenous streaks induced by 5-fluorouracil

To the Editor: Hrushesky1Hrushesky W.J. Unusual pigmentary changes associated with 5-fluorouracil therapy.Cutis. 1980; 26: 181-182PubMed Google Scholar was the first to report hyperpigmentation of the skin immediately overlying veins used for multiple 5-fluorouracil (5-FU) infusions and used the term “serpentine supravenous fluorouracil hyperpigmentation” for this entity.A 30-year-old male developed asymptomatic serpiginous hyperpigmentation characteristically overlying the right cephalic, basilic, median cubital veins, and median vein of forearm (Fig 1) after receiving 2 cycles of adjuvant 5-FU as continuous intravenous infusion for rectal adenocarcinoma. There was no clinical evidence of thrombophlebitis, and these veins were still patent. The histopathology of the involved skin showed an increase in the epidermal melanin content and melanin incontinence into the dermis (Fig 2). The patient received a third cycle of 5-FU that did not worsen the pigmentation.Fig 2Photomicrograph showing increased epidermal melanin content and melanin incontinence into the dermis. (Hematoxylin-eosin stain; original magnification: ×100.)View Large Image Figure ViewerDownload (PPT)The exact mechanism of this phenomenon is unknown, but it has been postulated that these cytotoxic agents cause endothelial injury. The agent then leaches from the vessel to the overlying epidermal melanocytes and interferes in melanosome packaging with the keratinocytes,2O'Daugherty D. Hyperpigmentation after cancer chemotherapy.Lancet. 1975; 2: 365Abstract Scopus (6) Google Scholar thereby resulting in hyperpigmentation of that skin.This is an isolated occurrence of 5-FU–induced serpentine supravenous streaks; in the absence of other dermatologic, hematologic, or gastrointestinal side effects, this is an extremely rare phenomenon. There is no specific treatment3Perlin E. Ahlgern J.D. Pigmentary effects from protracted infusion of 5-fluorouracil.Int J Dermatol. 1991; 30: 43-44Crossref PubMed Scopus (18) Google Scholar for the pigmentary streaks induced by 5-FU. In time, the pigmentation disappears and may not warrant discontinuation of the drug. To the Editor: Hrushesky1Hrushesky W.J. Unusual pigmentary changes associated with 5-fluorouracil therapy.Cutis. 1980; 26: 181-182PubMed Google Scholar was the first to report hyperpigmentation of the skin immediately overlying veins used for multiple 5-fluorouracil (5-FU) infusions and used the term “serpentine supravenous fluorouracil hyperpigmentation” for this entity. A 30-year-old male developed asymptomatic serpiginous hyperpigmentation characteristically overlying the right cephalic, basilic, median cubital veins, and median vein of forearm (Fig 1) after receiving 2 cycles of adjuvant 5-FU as continuous intravenous infusion for rectal adenocarcinoma. There was no clinical evidence of thrombophlebitis, and these veins were still patent. The histopathology of the involved skin showed an increase in the epidermal melanin content and melanin incontinence into the dermis (Fig 2). The patient received a third cycle of 5-FU that did not worsen the pigmentation. The exact mechanism of this phenomenon is unknown, but it has been postulated that these cytotoxic agents cause endothelial injury. The agent then leaches from the vessel to the overlying epidermal melanocytes and interferes in melanosome packaging with the keratinocytes,2O'Daugherty D. Hyperpigmentation after cancer chemotherapy.Lancet. 1975; 2: 365Abstract Scopus (6) Google Scholar thereby resulting in hyperpigmentation of that skin. This is an isolated occurrence of 5-FU–induced serpentine supravenous streaks; in the absence of other dermatologic, hematologic, or gastrointestinal side effects, this is an extremely rare phenomenon. There is no specific treatment3Perlin E. Ahlgern J.D. Pigmentary effects from protracted infusion of 5-fluorouracil.Int J Dermatol. 1991; 30: 43-44Crossref PubMed Scopus (18) Google Scholar for the pigmentary streaks induced by 5-FU. In time, the pigmentation disappears and may not warrant discontinuation of the drug.

Hair removal with an 800-nm pulsed diode laser

Background and Objective: Laser hair removal is a relatively new procedure. Our purpose was to study the efficacy and safety of a high-power, pulsed diode laser array for removing unwanted hair. Methods: A total of 38 subjects were treated with a prototype of the 800-nm diode laser system. Fluences ranging from 10 to 40 J/cm2 (mean, 33.4 J/cm2) were used and 1 to 4 treatments (mean, 2.7) were performed. Evaluation of hair loss was performed at least 4 months after the last treatment (mean, 8.7 months) by a blinded assessment of clinical photographs. Results: A total of 59% of the subjects had only sparse hair regrowth at the final follow-up. Higher fluences and multiple treatments produced greater long-term efficacy. Transient pigmentary changes occurred in 29% of the subjects and were more common in darker skin types IV to VI (P = .047). Conclusion: The 800-nm diode laser is an efficient and safe technique for hair reduction. Adverse pigmentary effects occur, but are transient. (J Am Acad Dermatol 2000;43:442–7.)

Biochemical and genetic studies of pigment-type switching.

Mutations that affect the balance between the synthesis of eumelanin and pheomelanin provide a powerful set of tools with which to understand general aspects of cell signaling. Previous work from our laboratory has demonstrated that pheomelanin synthesis is triggered by the ability of Agouti protein to inhibit signaling through the Melanocortin 1 receptor (Mc1r). In a bioassay based on the Xenopus Mc1r, Agouti protein has two effects, competitive inhibition of receptor occupancy by alpha-MSH and down-regulation of receptor signaling, which are mediated separately by domains in the amino- and carboxy-terminal regions of Agouti protein, respectively. Recently, we have used the genetics of pigmentation as an in vivo system to screen for and analyze other mutations in the Agouti-melanocortin pathway. The pigmentary effects of Agouti are suppressed by the previously existing coat-color mutations mahogany (mg), mahoganoid (md), and Umbrous (U). Double mutant studies, with animals deficient for the Mc1r or those which carry Ay, indicate that mg and md are genetically upstream of the Mc1r, and can suppress the effects of Ay on both pigmentation and body weight. Positional cloning has recently identified the gene mutated in mahogany as a single transmembrane-spanning protein whose ectodomain is orthologous to human Attractin (Atrn).

Molecular pharmacology of Agouti protein in vitro and in vivo.

Agouti protein and Agouti-related protein (Agrp) are paracrine signaling molecules that act by antagonizing the effects of melanocortins, and several alternatives have been proposed to explain their mechanisms of action. Genetic crosses in a sensitized background uncover a phenotypic difference between overexpression of Agouti and loss of Mc1r function, demonstrate that a functional Mc1r is required for the pigmentary effects of Agouti, and suggest that Agouti protein can act as an agonist of the Mc1r in a way that differs from alpha-MSH stimulation. In vitro, Agouti protein inhibits melanocortin action by two mechanisms: competitive antagonism that depends on the carboxyterminus of the protein, and downregulation of melanocortin receptor signaling that depends on the aminoterminus. Our findings provide evidence of a novel signaling mechanism whereby alpha-MSH and Agouti protein function as independent ligands that inhibit each other's binding and transduce opposite signals through a single receptor.

Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo.

Agouti protein and Agouti-related protein (Agrp) are paracrine-signaling molecules that normally regulate pigmentation and body weight, respectively. These proteins antagonize the effects of alpha-melanocyte-stimulating hormone (alpha-MSH) and other melanocortins, and several alternatives have been proposed to explain their biochemical mechanisms of action. We have used a sensitive bioassay based on Xenopus melanophores to characterize pharmacologic properties of recombinant Agouti protein, and have directly measured its cell-surface binding to mammalian cells by use of an epitope-tagged form (HA-Agouti) that retains biologic activity. In melanophores, Agouti protein has no effect in the absence of alpha-MSH, but its action cannot be explained solely by inhibition of alpha-MSH binding. In 293T cells, expression of the Mc1r confers a specific, high-affinity binding site for HA-Agouti. Binding is inhibited by alpha-MSH, or by Agrp, which indicates that alpha-MSH and Agouti protein bind in a mutually exclusive way to the Mc1r, and that the similarity between Agouti protein and Agrp includes their binding sites. The effects of Agouti and the Mc1r in vivo have been examined in a sensitized background provided by the chinchilla (Tyrc-ch) mutation, which uncovers a phenotypic difference between overexpression of Agouti in lethal yellow (Ay/a) mice and loss of Mc1r function in recessive yellow (Mc1re/Mc1re) mice. Double and triple mutant studies indicate that a functional Mc1r is required for the pigmentary effects of Agouti, and suggest that Agouti protein can act as an agonist of the Mc1r in a way that differs from alpha-MSH stimulation. These results resolve questions regarding the biochemical mechanism of Agouti protein action, and provide evidence of a novel signaling mechanism whereby alpha-MSH and Agouti protein or Agrp function as independent ligands that inhibit each other's binding and transduce opposite signals through a single receptor.

Melanin-Concentrating Hormone (MCH) Antagonizes the Effects of α-MSH and Neuropeptide E-I on Grooming and Locomotor Activities in the Rat

Sanchez, M., B. I. Baker and M. Celis. Melanin-concentrating hormone (MCH) antagonizes the effects of α-MSH and neuropeptide E-I on grooming and locomotor activities in the rat. Peptides 18(3) 393–396, 1997.—The intraventricular (ICV) administration of the neuropeptide melanocyte stimulating hormone (α-MSH) is known to elicit a series of behaviors in the rat which include excessive grooming and other motor activities. In bony fish, the pigmentary effects of α-MSH can be antagonized by the neuropeptide melanin-concentrating hormone (MCH). We therefore examined whether MCH or its sister peptide neuropeptide E-I (NEI), derived from the same precursor molecule, would modulate the effect of α-MSH on grooming and motor activity in the rat, or perhaps elicit some responses of their own. Rats were injected ICV with either artificial cerebrospinal fluid, α-MSH, MCH, NEI, or with two peptides together, and behavioral responses were monitored over the next 65 min. The ICV injection of 1 μg MSH significantly enhanced grooming behavior. NEI at the same dose increased grooming, rearing, and locomotor activities. MCH alone had no behavioral effects but it annulled the behavioral responses induced by either α-MSH or NEI. α-MSH also antagonized the locomotor and rearing behavior induced by NEI. The physiological significance of these observations is discussed.

Pigmentary Effects from the Protracted Infusion of 5‐Fluorouracil

Pigmentary Effects from the Protracted Infusion of 5‐Fluorouracil

Comparative behavioral, biochemical and pigmentary effects of MPTP, MPP + and paraquat in rana pipiens

We demonstrate that injections of 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP), 1-methyl-4-phenyl-pyridinium ion (MPP +) and Paraquat (PQ +) produce in Rana Pipiens different behavioral, biochemical and skin pigmentation changes. MPTP causes in frogs the main symptoms of Parkinsonism (rigidity, akinesia and tremor) and it darkens the skin of animals. It also decreases brain and, less so, adrenal medulla dopamine. These effects are blocked by Pargyline. MPP + causes the same symptoms but more rapidly. In contrast, skin pigmentation is clearly lightened. Brain and particularly adrenal dopamine reserves are nearly abolished. Pargyline increases these effects. Paraquat, in a cumulative fashion, eventually causes the same behavioral changes and a slight increase in pigmentation. It initially produces an increase in brain and adrenal dopamine concentrations, but later a significant dopamine concentration decrease. Pargyline potentiates these long term effects, blocks the dopamine increase, but reverses the PQ + effect upon melanin, producing the same depigmentation as MPP + alone.

The occurrence of vitiligo after psoralens and ultraviolet A therapy

The ability of photochemotherapy with 8-methoxypsoralen in conjunction with high-intensity long-wave ultraviolet light (PUVA) to stimulate melanogenesis is well known. This effect on the pigmentary system is evidenced by the diffuse tanning of clinically normal skin in PUVA-treated patients with psoriasis and other disorders, as well as by the repigmentation of lesions in vitiligo. It is now recognized that there may be additional pigmentary effects, resulting in clinical lesions such as PUVA mottling, PUVA lentigines, and localized hypopigmentation. We have documented the occurrence of yet another association with PUVA therapy--the paradoxical appearance of widespread hypopigmentation consistent with vitiligo in three PUVA-treated patients, one with psoriasis and two with mycosis fungoides. Histologic and ultrastructural findings are presented.

Biodegradation of α-MSH and derived peptides by rat brain extracts, and by rat and human serum

The peptides α-MSH and MSH/ACTH 4–10 were degraded by rat brain extracts and serum to yield free amino acids among the end-products. Breakdown of these two peptides was double that of a related synthetic hexapeptide Met (0)-Glu-His-Phe-D-Lys-Phe. No significant breakdown of the hexapeptide occurred after incubation with human serum; it also had almost negligible pigmentary effects in vivo and in vitro when compared to α-MSH. The patterns of amino acid release indicate possible endopeptidase cleavage at Phe-Arg in α-MSH followed by secondary exopeptidase action to release free amino acids. For the hexapeptide, the primary cleavage point occurred at the -His 3-Phe 4 bond. The stability of this analog in human sera, coupled with its lower rate of degradation in the CNS, may contribute to its more potent behavioral actions in vivo.

Phenocopies of pigmentary and behavioral effects of the yellow mutant in Drosophila induced by alpha-dimethyltyrosine.

alpha-Dimethyltyrosine induces a phenocopy of the body color mutant yellow when fed to larvae of Drosophila melanogaster. The compound also induces changes in male courtship behavior which are similar to the effects of the mutant gene.

Thyroid stimulating and pigmentary effects of synthetic peptides related to α-MSH and ACTH

Seven synthetic peptides related to α-MSH and ACTH and eleven stereoisomeric fragments of α-MSH (sequence 6–10) were tested for their thyroid stimulating effects. This TSH-like activity was determined by following 131I release in mice injected with 131I and treated with thyroxine. N-α-acetyl-β-corticotropin-(1–24)-tetracosapeptide and β-corticotropin-(1–24)-tetracosapeptide hydrazide had the highest MSH activity and elicited the greatest effects on the blood levels of 131I. The α-MSH-(7–13)-heptapeptide which had a moderate MSH activity, also caused a significant stimulation of 131I release in mice. On the other hand, β-corticotropin-(11–24)-tetradecapeptide, which had virtually no MSH activity, possessed some TSH-like activity. D-His-D-Phe-D-Arg-D-Trp-Gly and the analogous L-pentapeptide, which were essentially free of MSH activity, had no effect on the thyroid at doses up to 100 μg. per mouse. Seven MSH-ACTH stereoisomers, which individually assayed up to 1,200 MSH U/mg., similarly had no effect on the thyroid, but L-His-D-Phe-L-Arg-L-Trp-Gly and three stereoisomers which had a low but definite MSH activity, did exert some TSH-like effects. These studies reveal that, although some relationship between MSH and TSH-like activity can be observed among peptides of the MSH-ACTH group, there is no definite correlation between these activities.