Tranexamic acid inhibits melanogenesis by activating the autophagy system in cultured melanoma cells.
Cho Yeong Hee,Park Jung Eun,Lim Do Sung,Lee Jung Sup
Journal of dermatological science
BACKGROUND:As interest in skin beauty increases, the development of new skin whitening agents has attracted substantial attention; however, the action mechanism of the agents developed so far remains largely unknown. Tranexamic acid (TXA) is commonly being used to reduce melanin synthesis in patients with melasma and also used as a raw material for functional whitening cosmetics, although its action mechanism is poorly understood. Autophagy has been well known to be essential for tissue homeostasis, adaptation to starvation, and removal of dysfunctional organelles or pathogens. Recent studies have shown that autophagy regulators might have prominent roles in the initial formation stage of the melanosome, a lysosome-related organelle synthesizing melanin pigments. However, there is still no direct evidence showing a relationship between the activation of the autophagy system and the melanogenesis. OBJECTIVE:To investigate whether TXA can inhibit melanogenesis through the activation of autophagy in a melanoma cell line. METHODS:B16-F1 melanoma cells were treated with TXA and the levels of autophagy- and melanogenesis-related proteins were determined by Western blottings. The direct effect of TXA-mediated autophagy activation on melanin production was further evaluated by transfecting the cells with 60 pmols of small interfering RNAs (siRNAs)-targeting the mechanistic target of rapamycin (mTOR) and the autophagy-related protein 5 (Atg5). RESULTS:The results of Western blottings showed that TXA enhanced the production of autophagy-related proteins such as mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK)1/2, Beclin-1, Atg12, and light chain 3 (LC3) I-II, whereas it decreased the synthesis of the mTOR complex. Confocal microscopy clearly showed that TXA treatment resulted in the formation of autophagosomes in B16-F1 cells, as revealed by immunostaining with an anti-LC3 antibody. The production of melanogenesis-associated proteins, including microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein 1 and 2 (TRP1/2), were clearly downregulated by the treatments with TXA. These results suggest that TXA can mediate a decrease in melanin synthesis by alleviating the production of tyrosinase and TRP1/2, along with lowered MITF protein levels. Furthermore, after treatment with TXA, siRNAs- targeting to mTOR and Atg5 increased melanin synthesis by 20% and 40%, respectively, compared to that in non-transfected cells, in a dose-dependent manner. These results further confirmed that TXA can inhibit melanogenesis by activating the autophagy system. CONCLUSION:Collectively, the results demonstrate that TXA can reduce melanin synthesis in melanoma B16-F1 cells by activating the ERK signaling pathway and the autophagy system.
Secreted Frizzled-Related Protein 2 (sFRP2) Functions as a Melanogenic Stimulator; the Role of sFRP2 in UV-Induced Hyperpigmentary Disorders.
Kim Misun,Han Jae Ho,Kim Jang-Hee,Park Tae Jun,Kang Hee Young
The Journal of investigative dermatology
In this study, we found that secreted frizzled-related protein 2 (sFRP2) is overexpressed in the hyperpigmentary skin of melasma and solar lentigo and in acutely UV-irradiated skin. To investigate the effect of sFRP2 on melanogenesis, normal human melanocytes were infected with sFRP2-lentivirus or sh-sFRP2. It was found that sFRP2 stimulates melanogenesis through microphthalmia-associated transcription factor and/or tyrosinase upregulation via β-catenin signaling. The stimulatory action of sFRP2 in pigmentation was further confirmed in melanocytes cocultured with fibroblasts and in ex vivo cultured skin. The findings suggest that sFRP2 functions as a melanogenic stimulator and that it plays a role in the development of UV-induced hyperpigmentary disorders.
Pigmentation and Pregnancy: Knowing What Is Normal.
Bieber Amy Kalowitz,Martires Kathryn J,Stein Jennifer A,Grant-Kels Jane M,Driscoll Marcia S,Pomeranz Miriam Keltz
Obstetrics and gynecology
Changes in melanocytic nevi during pregnancy are frequently attributed to the new hormonal milieu and are dismissed without concern for malignancy. Recent studies suggest that pregnancy itself does not induce significant change in nevi, and delays in the assessment of changing moles may contribute to the often more advanced nature of melanomas diagnosed during or soon after pregnancy. Nevi on the breasts and abdomen can grow as a result of skin expansion, but studies have found no significant changes in nevi located in more stable areas such as the back or lower extremities. There is also insufficient evidence to support the notion that nevi darken during pregnancy. As such, any changing nevus that would raise concern for malignancy in a nonpregnant patient should do so in a pregnant patient as well. Pregnancy can, however, induce physiologic pigmentary changes that are often worrisome to both patients and physicians. These benign changes include melasma, pigmentary demarcation lines, secondary areola, and linea nigra as well as other less common findings. It is important for physicians to recognize these changes as physiologic to provide adequate reassurance to their patients and avoid unnecessary stress.
Sun-protective behaviors in patients with cutaneous hyperpigmentation: A cross-sectional study.
Maymone Mayra B C,Neamah Hind H,Wirya Stephen A,Patzelt Nicole M,Zancanaro Pedro Q,Vashi Neelam A
Journal of the American Academy of Dermatology
BACKGROUND:Disorders of hyperpigmentation are seen commonly in clinical practice. Despite numerous studies investigating sun-protective habits among healthy persons, little is known about these behaviors within patient populations with hyperpigmentation disorders. OBJECTIVE:We sought to examine photo-protective behaviors and their associations in individuals with disorders of hyperpigmentation. METHODS:This cross-sectional study was conducted with 404 adults who complained of cutaneous hyperpigmentation. RESULTS:About 67.5% reported using a product containing sunscreen, and 91% endorsed using one with a sun protection factor of 21 or higher. Among the participants, 48.5% were not sure if their sunscreen provided broad-spectrum protection, and only 7.6% reapplied every 2 hours. The odds of a patient with melasma using sunscreen were 6.7 times the odds of a patient with postinflammatory hyperpigmentation using sunscreen (P < .001). Additional predictors for sunscreen use were female sex (OR = 3.8, P = .0004) and disease duration of ≥1 year (OR = 2.1, P = .003). In a multivariate analysis, the odds ratio of sunscreen use among African Americans compared to whites was 0.31 (P = .008). LIMITATIONS:Limitations included recall bias, question misinterpretation, and reporter bias. CONCLUSION:Patients diagnosed with postinflammatory hyperpigmentation, men, and those with disease duration <1 year reported lower sunscreen usage. These groups might benefit from increased counseling on sun-protective behaviors.
Molecular mechanisms of green tea polyphenols with protective effects against skin photoaging.
Roh Eunmiri,Kim Jong-Eun,Kwon Jung Yeon,Park Jun Seong,Bode Ann M,Dong Zigang,Lee Ki Won
Critical reviews in food science and nutrition
Whereas green tea has historically been consumed in high quantities in Northeast Asia, its popularity is also increasing in many Western countries. Green tea is an abundant source of plant polyphenols exhibiting numerous effects that are potentially beneficial for human health. Accumulating evidence suggests that green tea polyphenols confer protective effects on the skin against ultraviolet (UV) irradiation-induced acceleration of skin aging, involving antimelanogenic, antiwrinkle, antioxidant, and anti-inflammatory effects as well as prevention of immunosuppression. Melanin pigmentation in the skin is a major defense mechanism against UV irradiation, but pigmentation abnormalities such as melasma, freckles, senile lentigines, and other forms of melanin hyperpigmentation can also cause serious health and aesthetic issues. Furthermore, UV irradiation initiates the degradation of fibrillar collagen and elastic fibers, promoting the process of skin aging through deep wrinkle formation and loss of tissue elasticity. UV irradiation-induced formation of free radicals also contributes to accelerated photoaging. Additionally, immunosuppression caused by UV irradiation plays an important role in photoaging and skin carcinogenesis. In this review, we summarize the current literature regarding the antimelanogenic, antiwrinkle, antioxidant, and immunosuppression preventive mechanisms of green tea polyphenols that have been demonstrated to protect against UV irradiation-stimulated skin photoaging, and gauge the quality of evidence supporting the need for clinical studies using green tea polyphenols as anti-photoaging agents in novel cosmeceuticals.
Recent Advances and Perspectives in Liposomes for Cutaneous Drug Delivery.
Carita Amanda C,Eloy Josimar O,Chorilli Marlus,Lee Robert J,Leonardi Gislaine Ricci
Current medicinal chemistry
The cutaneous route is attractive for the delivery of drugs in the treatment of a wide variety of diseases. However the stratum corneum (SC) is an effective barrier that hampers skin penetration. Within this context, liposomes emerge as a potential carrier for improving topical delivery of therapeutic agents. In this review, we aimed to discuss key aspects for the topical delivery by drug-loaded liposomes. Phospholipid type and phase transition temperature have been shown to affect liposomal topical delivery. The effect of surface charge is subject to considerable variation depending on drug and composition. In addition, modified vesicles with the presence of components for permeation enhancement, such as surfactants and solvents, have been shown to have a considerable effect. These liposomes include: Transfersomes, Niosomes, Ethosomes, Transethosomes, Invasomes, coated liposomes, penetration enhancer containing vesicles (PEVs), fatty acids vesicles, Archaeosomes and Marinosomes. Furthermore, adding polymeric coating onto liposome surface could influence cutaneous delivery. Mechanisms of delivery include intact vesicular skin penetration, free drug diffusion, permeation enhancement, vesicle adsorption to and/or fusion with the SC, trans-appendageal penetration, among others. Finally, several skin conditions, including acne, melasma, skin aging, fungal infections and skin cancer, have benefited from liposomal topical delivery of drugs, with promising in vitro and in vivo results. However, despite the existence of some clinical trials, more studies are needed to be conducted in order to explore the potential of liposomes in the dermatological field.
Downregulation of melanogenesis: drug discovery and therapeutic options.
Pillaiyar Thanigaimalai,Manickam Manoj,Jung Sang-Hun
Drug discovery today
Melanin, primarily responsible in humans for hair, eye and skin pigmentation, is produced by melanocytes through a process called melanogenesis. However, the abnormal accumulation of melanin causes dermatological problems such as café-au-lait macules ephelides (freckles), solar lentigo (age spots) and melasma, as well as cancer and vitiligo. Hence the regulation of melanogenesis is very important for treating hyperpigmentary disorders. Numerous antimelanogenic agents that target tyrosinase activity and/or stability, melanosome maturation, transfer and trafficking, or melanogenesis-related signaling pathways have been developed. This article reviews recent advances in research and development of human tyrosinase and melanogenesis-related signaling pathway inhibitors. Attempts have been made to provide a complete description of the mechanism of action of inhibitors on various melanogenesis signaling pathways.
α-Viniferin Improves Facial Hyperpigmentation via Accelerating Feedback Termination of cAMP/PKA-Signaled Phosphorylation Circuit in Facultative Melanogenesis.
Yun Cheong-Yong,Mi Ko Seon,Pyo Choi Yong,Kim Beom Joon,Lee Jungno,Mun Kim Jae,Kim Ju Yeon,Song Jin Yong,Kim Song-Hee,Hwang Bang Yeon,Tae Hong Jin,Han Sang-Bae,Kim Youngsoo
cAMP up-regulates microphthalmia-associated transcription factor subtype M (MITF-M) and tyrosinase (Tyro) in the generation of heavily pigmented melanosomes. Here, we communicate a therapeutic mechanism of hyperpigmented disorder by α-viniferin, an active constituent of . We used cAMP-elevated melanocyte cultures or facial hyperpigmented patches for pigmentation assays, and applied immunoprecipitation, immunobloting, RT-PCR or reporter gene for elucidation of the antimelanogenic mechanism. or α-viniferin inhibited melanin production in α-melanocyte-stimulating hormone (α-MSH)-, histamine- or cell-permeable cAMP-activated melanocyte cultures. Moreover, topical application with containing α-viniferin, a standard in quality control, decreased melanin index on facial melasma and freckles in patients. As a molecular basis, α-viniferin accelerated protein kinase A (PKA) inactivation via the reassociation between catalytic and regulatory subunits in cAMP-elevated melanocytes, a feedback loop in the melanogenic process. α-Viniferin resultantly inhibited cAMP/PKA-signaled phosphorylation of cAMP-responsive element-binding protein (CREB) coupled with dephosphorylation of cAMP-regulated transcriptional co-activator 1 (CRTC1), thus down-regulating expression of MITF-M or Tyro gene with decreased melanin pigmentation. This study assigned PKA inactivation, a feedback termination in cAMP-induced facultative melanogenesis, as a putative target of α-viniferin in the treatment of melanocyte-specific hyperpigmented disorder. Finally, containing α-viniferin was approved as an antimelanogenic agent with topical application in skin hyperpigmentation.
Fibronectin-Containing Extracellular Vesicles Protect Melanocytes against Ultraviolet Radiation-Induced Cytotoxicity.
Bin Bum-Ho,Kim Dae-Kyum,Kim Nan-Hyung,Choi Eun-Jeong,Bhin Jinhyuk,Kim Sung Tae,Gho Yong Song,Lee Ai-Young,Lee Tae Ryong,Cho Eun-Gyung
The Journal of investigative dermatology
Skin melanocytes are activated by exposure to UV radiation to secrete melanin-containing melanosomes to protect the skin from UV-induced damage. Despite the continuous renewal of the epidermis, the turnover rate of melanocytes is very slow, and they survive for long periods. However, the mechanisms underlying the survival of melanocytes exposed to UV radiation are not known. Here, we investigated the role of melanocyte-derived extracellular vesicles in melanocyte survival. Network analysis of the melanocyte extracellular vesicle proteome identified the extracellular matrix component fibronectin at a central node, and the release of fibronectin-containing extracellular vesicles was increased after exposure of melanocytes to UVB radiation. Using an anti-fibronectin neutralizing antibody and specific inhibitors of extracellular vesicle secretion, we demonstrated that extracellular vesicles enriched in fibronectin were involved in melanocyte survival after UVB radiation. Furthermore, we observed that in the hyperpigmented lesions of patients with melasma, the extracellular space around melanocytes contained more fibronectin compared with normal skin, suggesting that fibronectin is involved in maintaining melanocytes in pathological conditions. Collectively, our findings suggest that melanocytes secrete fibronectin-containing extracellular vesicles to increase their survival after UVB radiation. These data provide important insight into how constantly stimulated melanocytes can be maintained in pathological conditions such as melasma.
Novel regulation of melanogenesis by adiponectin via the AMPK/CRTC pathway.
Bang Seunghyun,Won Kwang Hee,Moon Hye-Rim,Yoo Hanju,Hong Areum,Song Youngsup,Chang Sung Eun
Pigment cell & melanoma research
Several studies observed that adiponectin, an important adipokine that improves glucose metabolism by regulating AMP-activated protein kinase (AMPK) signaling, is dermatologically beneficial. In our recent microarray data, we found that adiponectin expression was lower in lesional skin than in non-lesional skin of melasma patients. Given that AMPK is a key adiponectin signaling mediator, we investigated the role of adiponectin and AICAR, a cell-permeable AMPK activator, in melanogenesis. We herein showed that adiponectin and AICAR downregulated MITF, tyrosinase, TRP-1, and DCT expression and reduced melanin content in normal human and mouse melanocytes. The depigmenting effect of adiponectin was mediated via AMPK activation, which induced the inhibitory phosphorylation of CREB-regulated transcription co-activators (CRTCs) and subsequent suppression of the novel CRTC/CREB pathway in melanocytes. These findings suggest that adiponectin and its analogs are useful as a clinical strategy for treating hyperpigmentation disorders.
Recent development of signaling pathways inhibitors of melanogenesis.
Pillaiyar Thanigaimalai,Manickam Manoj,Jung Sang-Hun
Human skin, eye and hair color rely on the production of melanin, depending on its quantity, quality, and distribution, Melanin plays a monumental role in protecting the skin against the harmful effect of ultraviolet radiation and oxidative stress from various environmental pollutants. However, an excessive production of melanin causes serious dermatological problems such as freckles, solar lentigo (age spots), melasma, as well as cancer. Hence, the regulation of melanin production is important for controlling the hyper-pigmentation. Melanogenesis, a biosynthetic pathway to produce melanin pigment in melanocyte, involves a series of intricate enzymatic and chemical catalyzed reactions. Several extrinsic factors include ultraviolet radiation and chemical drugs, and intrinsic factors include molecules secreted by surrounding keratinocytes or melanocytes, and fibroblasts, all of which regulate melanogenesis. This article reviews recent advances in the development of melanogenesis inhibitors that directly/indirectly target melanogenesis-related signaling pathways. Efforts have been made to provide a description of the mechanism of action of inhibitors on various melanogenesis signaling pathways.
Anti-melanogenic effects of oyster hydrolysate in UVB-irradiated C57BL/6J mice and B16F10 melanoma cells via downregulation of cAMP signaling pathway.
Han Jae Hyeong,Bang Joon Sok,Choi Yeung Joon,Choung Se-Young
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Pacific oyster (Crassostrea gigas) has been used to treat pigmentary disorders such as freckles, melasma, and moles in Korea. AIM OF THE STUDY:We aimed to investigate the inhibitory effects of oyster hydrolysate (OH) on melanogenesis in B16F10 melanoma cells and UVB-irradiated C57BL/6J mice. MATERIAL AND METHODS:The molecular weight distribution and peptide sequences of OH were detected using MALDI-TOF and UHPLC. To evaluate the anti-melanogenic effects of OH, cell viability, melanin content, tyrosinase activity, intracellular cyclic adenosine monophosphate (cAMP) and protein expressions levels were measured in B16F10 cells. In addition, OH was orally administered to UVB-irradiated mice for 9 weeks. After sacrificing the mice, the whitening effects of OH were evaluated based on histological observations and protein expression levels. RESULTS:In B16F10 cells, OH decreased melanin content and tyrosinase activity in a dose-dependent manner. OH exhibited anti-melanogenic activities via downregulation of cAMP signaling pathway, which consequently decreased melanin synthesis. In UVB-irradiated mice groups, OH decreased the number of active melanocytes and melanin granules. The expression of tyrosinase-related proteins and microphthalmia-associated transcription factor (MITF) decreased in the OH-administered groups. CONCLUSIONS:These results show that OH inhibits melanin synthesis in B16F10 cells via downregulation of cAMP signaling pathway and in UVB-irradiated mice, by decreasing the number of active melanocytes and melanin granules.
Beauvericin inhibits melanogenesis by regulating cAMP/PKA/CREB and LXR-α/p38 MAPK-mediated pathways.
Lee Seung Eun,Park See-Hyoung,Oh Sae Woong,Yoo Ju Ah,Kwon Kitae,Park Se Jung,Kim Jangsoon,Lee Hak Sung,Cho Jae Youl,Lee Jongsung
Melanogenesis is the process of production of melanin pigments that are responsible for the colors of skin, eye, and hair and provide protection from ultraviolet radiation. However, excessive levels of melanin formation cause hyperpigmentation disorders such as freckles, melasma, and age spots. Liver X receptors (LXR) are nuclear oxysterol receptors belonging to the family of ligand-activated transcription factors and physiological regulators of lipid and cholesterol metabolism. In the skin, activation of LXRs stimulates differentiation of keratinocytes and augments lipid synthesis in sebocytes. However, the function of LXRs in melanogenesis has not been clearly elucidated. In addition, although beauvericin, a well-known mycotoxin primarily isolated from several fungi, has various biological properties, its involvement in melanogenesis has not been reported. Therefore, in this study, we examined the effects of beauvericin on melanogenesis and its molecular mechanisms. Beauvericin decreased melanin content and tyrosinase activity without any cytotoxicity. Beauvericin also reduced protein levels of MITF, tyrosinase, TRP1, and TRP2. In addition, beauvericin suppressed cAMP-PKA-CREB signaling and upregulated expression of LXR-α, resulting in the suppression of p38 MAPK. Our results indicate that beauvericin attenuates melanogenesis by regulating both cAMP/PKA/CREB and LXR-α/p38 MAPK pathways, consequently leading to a reduction of melanin levels.
De Novo Molecular Design of a Novel Octapeptide That Inhibits In Vivo Melanogenesis and Has Great Transdermal Ability.
Feng Lan,Shi Nannan,Cai Shasha,Qiao Xue,Chu Peng,Wang Hui,Long Feida,Yang Huaixin,Yang Yongliang,Wang Yipeng,Yu Haining
Journal of medicinal chemistry
Cutaneous hyperpigmentation from excess melanogenesis causes serious pigmentary disorders and even melasma. Short peptides (SPs) are garnering attention lately owing to their therapeutic potential in dermatological diseases and low systemic side effects. Here, we show an octapeptide, ansin2, designed de novo from antioxidant SPs we previously reported, significantly inhibiting melanogenesis in B16 cells by decreasing tyrosinase production via regulating the MITF pathway. Ansin2 could also inhibit tyrosinase function by covering its catalytic pocket, which was simulated in docking and LIGPLOT studies. Topical application of ansin2 exhibited evident protection in UVB-induced pigmentation in guinea pig models both in terms of prophylaxis and treatment. Interestingly, unlike other hydrophilic and peptidic drugs that need delivery systems, ansin2 can be efficiently delivered topically to the epidermis and dermis per se without an affiliated moiety. Given that ansin2 lacks unwanted toxicities and immunogenicity, it holds great potential in treating hyperpigmentation in the cosmetics and pharmaceutical industries.
Structural studies of plasmin inhibition.
Wu Guojie,Quek Adam J,Caradoc-Davies Tom T,Ekkel Sue M,Mazzitelli Blake,Whisstock James C,Law Ruby H P
Biochemical Society transactions
Plasminogen (Plg) is the zymogen form of the serine protease plasmin (Plm), and it plays a crucial role in fibrinolysis as well as wound healing, immunity, tissue remodeling and inflammation. Binding to the targets via the lysine-binding sites allows for Plg activation by plasminogen activators (PAs) present on the same target. Cellular uptake of fibrin degradation products leads to apoptosis, which represents one of the pathways for cross-talk between fibrinolysis and tissue remodeling. Therapeutic manipulation of Plm activity plays a vital role in the treatments of a range of diseases, whereas Plm inhibitors are used in trauma and surgeries as antifibrinolytic agents. Plm inhibitors are also used in conditions such as angioedema, menorrhagia and melasma. Here, we review the rationale for the further development of new Plm inhibitors, with a particular focus on the structural studies of the active site inhibitors of Plm. We compare the binding mode of different classes of inhibitors and comment on how it relates to their efficacy, as well as possible future developments.
Aminoluciferin 4-hydroxyphenyl amide enables bioluminescence detection of endogenous tyrosinase.
Tang Chunchao,Jin Lei,Lin Yuxing,Su Jing,Sun Yingai,Liu Pan,Li Qi,Wang Guankai,Zhang Zheng,Du Lupei,Li Minyong
Organic & biomolecular chemistry
Tyrosinase, a copper-containing enzyme existing widely in plants, animals and microorganisms, usually serves as an important biomarker in melanoma, and is also related to hyperpigmentation of the skin, melasma, age spots and albinism. At present, only one bioluminescent probe has been applied to image tyrosinase in cells. Thus, it's of great significance to develop a new bioluminescent probe that can detect tyrosinase in living cells and in live animals. In the current work, we report a new BL probe, TyrBP-3, which not detect tyrosinase in vitro and in living cells, but can also visualize the level of tyrosinase activity in tumors of living animals. In summary, TyrBP-3 is the first bioluminescent probe that can image tyrosinase on a cellular level. Hence, we anticipate that TyrBP-3 can be a good tool to monitor tyrosinase in complex biosystems in the future.
Platelet-rich plasma, a powerful tool in dermatology.
Merchán William H,Gómez Lina A,Chasoy María E,Alfonso-Rodríguez Camilo A,Muñoz Ana L
Journal of tissue engineering and regenerative medicine
Platelet-rich plasma (PRP), a platelet concentrate contained in a small volume of plasma, has become a promising option in the last decade to treat different diseases related to the skin due to its high concentration of growth factors. When it is of autologous origin, it decreases the probability of suffering adverse reactions and transfusion-transmitted infections, thus it is an optimal and safe therapy for the patient. PRP has been used in the treatment of several dermatological conditions such as acne, alopecia, and skin ulcers. Its use has also extended to other skin conditions such as melasma, hyperpigmentation, and burns, where it stimulates tissue repair and regeneration. The purpose of this article is to review the management and treatment of different dermatological alterations with PRP. Although there are a variety of studies that support the use of PRP, more research is needed to standardise the protocols for obtaining, processing, and applying it as well as understanding the biological and molecular bases of its functioning.
Inhibitors of Melanogenesis: An Updated Review.
Pillaiyar Thanigaimalai,Namasivayam Vigneshwaran,Manickam Manoj,Jung Sang-Hun
Journal of medicinal chemistry
Melanins are pigment molecules that determine the skin, eye, and hair color of the human subject to its amount, quality, and distribution. Melanocytes synthesize melanin and provide epidermal protection from various stimuli, such as harmful ultraviolet radiation, through the complex process called melanogenesis. However, serious dermatological problems occur when there is excessive production of melanin in different parts of the human body. These include freckles, melasma, senile lentigo, pigmented acne scars, and cancer. Therefore, controlling the production of melanin is an important approach for the treatment of pigmentation related disorderes. In this Perspective, we focus on the inhibitors of melanogenesis that directly/indirectly target a key enzyme tyrosinase as well as its associated signaling pathways.
Emerging role of dermal compartment in skin pigmentation: comprehensive review.
Kapoor R,Dhatwalia S K,Kumar R,Rani S,Parsad D
Journal of the European Academy of Dermatology and Venereology : JEADV
The variations in human skin colour mainly occur due to differences in the distribution of melanin pigment throughout the body, synthesized by epidermal melanocytes which are further taken up by keratinocytes present in epidermis. Recently, it has been discovered that besides these cells, dermis derived fibroblast factors also play a prominent role in regulating skin pigmentation. There exists a signal crosstalk between epidermal melanocytes, keratinocytes and dermal fibroblasts and any impairment in these signalling pathways may give rise to pigmentary disorders. Vitiligo is a hypopigmentary disorder and alteration in the expression level of several fibroblast-specific factors has been reported in the lesional skin of vitiligo patients. In such patients, there is decrease in the expression levels of factors such as basic fibroblast growth factor, stem cell factor (SCF) and keratinocyte growth factor (KGF) along with a steep increase in the expression levels of Dickkopf 1. Patients affected with hyperpigmentary disorder like melasma exhibit a marked increase in SCF and KGF expression levels leading to increase in melanin production and those affected with solar lentigo experience upregulation in the expression levels of SCF, KGF and HGF (hepatocyte growth factor). Hence, we conclude that new therapeutic strategies can be adopted to cure these pigmentary disorders by targeting factors involved in crosstalk signalling between epidermal melanocytes, keratinocytes and dermal fibroblasts.
The Polyamine Putrescine Promotes Human Epidermal Melanogenesis.
Sridharan Aishwarya,Shi Meng,Leo Vonny Ivon,Subramaniam Nagavidya,Lim Thiam Chye,Uemura Takeshi,Igarashi Kazuei,Tien Guan Steven Thng,Tan Nguan Soon,Vardy Leah A
The Journal of investigative dermatology
Hyperpigmentary conditions can arise when melanogenesis in the epidermis is misregulated. Understanding the pathways underlying melanogenesis is essential for the development of effective treatments. Here, we report that a group of metabolites called polyamines are important in the control of melanogenesis in human skin. Polyamines are cationic molecules present in all cells and are essential for cellular function. We report that polyamine regulator ODC1 is upregulated in melanocytes from melasma lesional skin. We report that the polyamine putrescine can promote pigmentation in human skin explants and primary normal human epidermal melanocytes through induction of tyrosinase which is rate-limiting for the synthesis of melanin. Putrescine supplementation on normal human epidermal melanocytes results in the activation of polyamine catabolism, which results in increased intracellular HO Polyamine catabolism is also increased in human skin explants that have been treated with putrescine. We further report that inhibition of polyamine catabolism prevents putrescine-induced promotion of tyrosinase levels and pigmentation in normal human epidermal melanocytes, showing that polyamine catabolism is responsible for the putrescine induction of melanogenesis. Our data showing that putrescine promotes pigmentation has important consequences for hyperpigmented and hypopigmented conditions. Further understanding of how polyamines control epidermal pigmentation could open the door for the development of new therapeutics.
Kumari Sulekha,Tien Guan Thng Steven,Kumar Verma Navin,Gautam Hemant K
Abnormally high production of melanin or melanogenesis in skin melanocytes results in hyperpigmentation disorders, such as melasma, senile lentigines or freckles. These hyperpigmentary skin disorders can significantly impact an individual's appearance, and may cause emotional and psychological distress and reduced quality of life. A large number of melanogenesis inhibitors have been developed, but most have unwanted side-effects. Further research is needed to better understand the mechanisms of hyperpigmentary skin disorders and to develop potent and safe inhibitors of melanogenesis. This review summarizes the current understanding of melanogenesis regulatory pathways, the potential involvement of the immune system, various drugs in current use, and emerging treatment strategies to suppress melanogenesis.
Recent Advances in Studies of Skin Color and Skin Cancer.
LaBerge Greggory S,Duvall Eric,Grasmick Zachary,Haedicke Kay,Galan Anjela,Leverett Jesse,Baswan Sudhir,Yim Sunghan,Pawelek John
The Yale journal of biology and medicine
The relationship between skin color and skin cancer is well established: the less melanin in one's skin the greater the risk for developing skin cancer. This review is in two parts. First, we summarize the current understanding of the cutaneous pigmentary system and trace melanin from its synthesis in the pigment cell melanosomes through its transfer to keratinocytes. We also present new methods for reducing melanin content in hyper-pigmented areas of skin such as solar lentigenes, melasma, and post-inflammatory hyperpigmentation. Second, we present evidence that at least one mechanism for the development of metastatic melanoma and other solid tumors is fusion and hybridization of leucocytes such as macrophages with primary tumor cells. In this scenario, hybrid cells express both the chemotactic motility of the leucocyte and the de-regulated cell division of the tumor cell, causing the cells to migrate a deadly journey to lymph nodes, distant organs, and tissues.
What's New in Pigmentary Disorders.
Zubair Raheel,Lyons Alexis B,Vellaichamy Gautham,Peacock Anjelica,Hamzavi Iltefat
Pigmentary disorders are common and can be very distressing to patients. There is a need for better, standardized therapies. The authors review the most recent data for topical, systemic, light, and laser treatments for vitiligo, melasma, and postinflammatory hyperpigmentation. There is a paucity of large-scale, well-designed, randomized, controlled trials for these treatments. Treatment options are often drawn from smaller trials and case series. The treatments described in this article are promising candidates for larger follow-up studies.
Cutaneous Interaction with Visible Light: What Do We Know.
Cohen Leah,Brodsky Merrick A,Zubair Raheel,Kohli Indermeet,Hamzavi Iltefat H,Sadeghpour Mona
Journal of the American Academy of Dermatology
Visible light has been used therapeutically in dermatology for years for a variety of cosmetic and medical indications, including skin rejuvenation and the treatment of inflammatory and neoplastic conditions, among others. Until recently, visible light was thought to be relatively inert compared to its spectral neighbors, ultraviolet and infrared radiation. However, recent literature has described the ability of visible light to cause erythema in light skin and pigmentary changes in individuals with darker skin types. Concern surrounding its potentially damaging cutaneous effects has been raised in both the medical community as well as in social media outlets. In this article, we provide an evidenced-based review describing what is currently known about visible light, focusing on its role in dermatologic diseases including disorders of hyperpigmentation such as melasma and post-inflammatory hyperpigmentation.
Premature cell senescence in human skin: Dual face in chronic acquired pigmentary disorders.
Bellei Barbara,Picardo Mauro
Ageing research reviews
Although senescence was originally described as an in vitro acquired cellular characteristic, it was recently recognized that senescence is physiologically and pathologically involved in aging and age-related diseases in vivo. The definition of cellular senescence has expanded to include the growth arrest caused by various cellular stresses, including DNA damage, inadequate mitochondria function, activated oncogene or tumor suppressor genes and oxidative stress. While senescence in normal aging involves various tissues over time and contributes to a decline in tissue function even with healthy aging, disease-induced premature senescence may be restricted to one or a few organs triggering a prolonged and more intense rate of accumulation of senescent cells than in normal aging. Organ-specific high senescence rate could lead to chronic diseases, especially in post-mitotic rich tissue. Recently, two opposite acquired pathological conditions related to skin pigmentation were described to be associated with premature senescence: vitiligo and melasma. In both cases, it was demonstrated that pathological dysfunctions are not restricted to melanocytes, the cell type responsible for melanin production and transport to surrounding keratinocytes. Similar to physiological melanogenesis, dermal and epidermal cells contribute directly and indirectly to deregulate skin pigmentation as a result of complex intercellular communication. Thus, despite senescence usually being reported as a uniform phenotype sharing the expression of characteristic markers, skin senescence involving mainly the dermal compartment and its paracrine function could be associated with the disappearance of melanocytes in vitiligo lesions and with the exacerbated activity of melanocytes in the hyperpigmentation spots of melasma. This suggests that the difference may arise in melanocyte intrinsic differences and/or in highly defined microenvironment peculiarities poorly explored at the current state of the art. A similar dualistic phenotype has been attributed to intratumoral stromal cells as cancer-associated fibroblasts presenting a senescent-like phenotype which influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. Here, we present a framework dissecting senescent-related molecular alterations shared by vitiligo and melasma patients and we also discuss disease-specific differences representing new challenges for treatment.
A cross-sectional report on melasma among Hispanic patients: Evaluating the role of oral tranexamic acid versus oral tranexamic acid plus hydroquinone.
Arreola Jauregui Ileana E,Huerta Rivera Gabriel,Soria Orozco Manuel,Meyer-Nava Silvia,Paniagua Santos Juan E,López Zaldo Juan B,Meyer-Nava Ilse,Madrid Carrillo Clara,Zaldo Rolón Iara E,Baeza Echeverría Aline E,Vázquez Huerta Minerva
Journal of the American Academy of Dermatology
Arginase-2, a miR-1299 target, enhances pigmentation in melasma by reducing melanosome degradation via senescence-induced autophagy inhibition.
Kim Nan-Hyung,Choi Soo-Hyun,Yi Nayoung,Lee Tae Ryong,Lee Ai-Young
Pigment cell & melanoma research
Expression profiles revealed miR-1299 downregulation concomitant with arginase-2 (ARG2) upregulation in hyperpigmented skin of melasma patients. Opposite regulation of tyrosinase and PMEL17 by miR-1299 and inverse relationship between miR-1299 and ARG2 expression denoted a role of miR-1299 in pigmentation with ARG2 as a miR-1299 target. ARG2 overexpression or knock-down in keratinocytes, the main source of ARG2 in epidermis, positively regulated tyrosinase and PMEL17 protein levels, but not mRNA levels or melanosome transfer. ARG2 overexpression in keratinocytes reduced autophagy equivalent to 3-MA, an autophagy inhibitor which also increased tyrosinase and PMEL17 protein levels, whereas ARG2 knock-down induced opposite results. Autophagy inducer rapamycin reduced ARG2-increased tyrosinase and PMEL17 protein levels. Also, autophagy was reduced in late passage-induced senescent keratinocytes showing ARG2 upregulation. ARG2, but not 3-MA, stimulated keratinocyte senescence. These results suggest that ARG2 reduces autophagy in keratinocytes by stimulating cellular senescence, resulting in skin pigmentation by reducing degradation of transferred melanosomes.
Cadherin 11 Involved in Basement Membrane Damage and Dermal Changes in Melasma.
Kim Nan-Hyung,Choi Soo-Hyun,Lee Tae Ryong,Lee Chang-Hoon,Lee Ai-Young
Basement membrane (BM) disruption and dermal changes (elastosis, collagenolysis, vascular ectasia) have been reported in melasma. Although ultraviolet (UV) irradiation can induce these changes, UV is not always necessary for melasma development. Cadherin 11 (CDH11), which is upregulated in some melasma patients, has previously been shown to stimulate melanogenesis. Because CDH11 action requires cell-cell adhesion between fibroblasts and melanocytes, BM disruption in vivo should facilitate this. The aim of this study was to examine whether CDH11 overexpression leads to BM disruption and dermal changes, independent of UV irradiation. Immunohistochemistry/immunofluorescence, real-time PCR, Western blotting, and zymography suggested that BM disruption/dermal changes and related factors were present in the hyperpigmented skin of CDH11-upregulated melasma patients and in CDH11-overexpressing fibroblasts/keratinocytes. The opposite was seen in CDH11-knockdown cells. UV irradiation of the cultured cells did not increase CDH11 expression. Collectively, these data demonstrate that CDH11 overexpression could induce BM disruption and dermal changes in melasma, regardless of UV exposure.
Tranexamic Acid in the Treatment of Melasma: A Review of the Literature.
Perper Marina,Eber Ariel Eva,Fayne Rachel,Verne Sebastian Hugo,Magno Robert James,Cervantes Jessica,ALharbi Mana,ALOmair Ibrahim,Alfuraih Abdulkarem,Nouri Keyvan
American journal of clinical dermatology
Melasma is a common acquired pigmentary disorder marked by irregular hyperpigmented macules or patches and most commonly occurs in women of darker skin color. It is a chronic often-relapsing condition that causes negative psychosocial effects in those affected. Current treatments such as hydroquinone, kojic acid, and retinoids, among others, demonstrate variable efficacy and side-effect profiles. We conducted a comprehensive literature review examining the use of tranexamic acid (TA), a well-known anti-fibrinolytic agent, in the treatment of melasma. TA delivered orally, topically, and through physical methods works via the inhibition of ultraviolet (UV)-induced plasmin activity in keratinocytes. Predefined search terms were entered into PubMed. Articles were then independently screened by two authors to include only those written in the English language and relating to human subjects with at least mild melasma. The search identified 28 articles, 15 of which met the criteria for full review. The review revealed that TA treatment for melasma is equally effective or more effective than other standard therapies and may induce fewer side effects. Our comprehensive review suggests that TA may be a promising treatment option for melasma because of its demonstrated effectiveness alone and in combination with other modalities as well as its limited side-effect profile.
How hormones may modulate human skin pigmentation in melasma: An in vitro perspective.
Melasma is a common acquired hyperpigmentary disorder occurring primarily in photo-exposed areas and mainly affecting women of childbearing age. To decipher the role of sex hormones in melasma, this viewpoint reviews the effects of sex hormones on cutaneous cells cultured in monolayers, in coculture, in 3D models and explants in the presence or the absence of UV. The data show that sex steroid hormones, especially oestrogen, can modulate in vitro pigmentation by stimulating melanocytes and keratinocyte pro-pigmentary factors, but not via fibroblast or mast cell activation. In vitro data suggest that oestrogen acts on endothelial cell count, which may in turn increase endothelin-1 concentrations. However, data on explants revealed that sex steroid even at doses observed during pregnancy cannot induce melanogenesis alone nor melanosome transfer but that it acts in synergy with UVB. In conclusion, we hypothesize that in predisposed persons, sex steroid hormones initiate hyperpigmentation in melasma by amplifying the effects of UV on melanogenesis via direct effects on melanocytes or indirect effects via keratinocytes and on the transfer of melanosomes. They also help to sustain hyperpigmentation by increasing the number of blood vessels and, in turn, the level of endothelin-1.
Exploring pathways for sustained melanogenesis in facial melasma: an immunofluorescence study.
Espósito A C C,Brianezi G,de Souza N P,Miot L D B,Marques M E A,Miot H A
International journal of cosmetic science
BACKGROUND:The physiopathology of epidermal hypermelanization in melasma is not completely understood. Several cytokines and growth factors are increased in skin with melasma, nevertheless, nor the pathways involved in the increased αMSH expression have been adequately evaluated, nor a model for sustained focal melanogenesis is available. OBJECTIVE:To explore stimulatory pathways for epidermal pigmentation in facial melasma related to αMSH: those linked to ultraviolet radiation, oxidative stress, inflammation, neural crest pigmentation cell differentiation and antagonism of αMSH. METHODS:Paired skin biopsies (3 mm) from 26 women with facial melasma and from normal adjacent skin (<2 cm far) were processed for immunofluorescence with markers for p53, p38, αMSH, MC1R, Melan-A, IL-1α, COX2, Wnt1, WIF-1 and ASIP. RESULTS:The fluorescence intensity in the skin from melasma was higher for MC1R, αMSH at epidermis as at melanocytes (P < 0.05). There were no differences between the sites in epidermal protein expression of COX2, IL-1α, p53, WIF-1 and ASIP (P > 0.1). P53 was expressed only in epidermis, without difference between sites (P = 0.92). WNT1 was remarkable in the epidermis of melasma (P < 0.01), but not in dermis. Positive p38 cells were prominent in the upper dermis of melasma (P < 0.01), despite no marking in epidermis. CONCLUSION:Melanogenesis in melasma involves epithelial secretion of αMSH and activation of the Wnt pathway; nevertheless, it seems to be independent of the stimulation by ultraviolet radiation/p53, IL-1α, COX2/PgE , WIF-1 and ASIP. Damaged cells at upper dermis suggest the role of senescence/autophagy in sustained pigmentation in melasma.
Increased expression of TGF-β protein in the lesional skins of melasma patients following treatment with platelet-rich plasma.
Hofny Eman R M,Hussein Mahmoud Rezk Abdelwahed,Ghazally Alaa,Ahmed Asmaa M,Abdel-Motaleb Amira A
Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology
: Melasma is a common acquired facial hyperpigmented skin disorder. Platelet-rich plasma (PRP) is autologous plasma containing higher than normal platelets concentrations. Recently, PRP has been used as a therapeutic modality in melasma with significant clinical improvement, possibly due to its abundant contents of growth factors such as TGF-β. The latter represents a natural multifunctional polypeptide that negatively regulates melanocyte differentiation and therefore reduces skin hyperpigmentation. To date, the expression pattern of TGF-β protein in skin of melasma patients following PRP injection is unknown. Here we hypothesize that "injection of PRP in the lesional skin of melasma patients is associated with alterations of TGF-β protein expression".: The study included 20 adult patients with melasma. Autologous PRP was delivered into the lesional skin either through microneedling or as intradermal microinjections. TGF-β protein expression was immunohistochemically examined in the perilesional and lesional skins before and after PRP treatment and in the healthy skins of nine volunteers (control group).: TGF-β protein was expressed within the epidermis, dermal adnexal structures, vascular endothelium, nerves and arrector pili muscle fibers of the healthy skins (control group), perilesional and lesional skins of melasma patients before and after treatment with PRP. Before treatment with PRP, the expression ofTGF-β protein in the lesional (1.26 ± 0.41) and perilesional (1.68 ± 0.51) skins of melasma patients were significantly lower than that in the healthy skins (2.26 ± 0.37, value<.05). After treatment with PRP, the expression of TGF-β protein was significantly increased in the lesional (2.15 ± 0.44) skin of melasma patients.: Our study provides the first indication about increased TGF-β protein expression in skin of melasma patients after PRP treatment. The alterations of TGF-β protein in skin of melasma patients not only support its roles in the development of this condition but also have some therapeutic ramifications.
Association between heterozygote Val92Met gene polymorphisms with incidence of melasma: a study of Javanese women population in Yogyakarta.
Suryaningsih Betty Ekawati,Sadewa Ahmad Hamim,Wirohadidjojo Yohanes Widodo,Soebono Hardyanto
Clinical, cosmetic and investigational dermatology
Melasma is an acquired hypermelanosis of the face. The pathogenesis of melasma is multifactorial and may be caused by interactions between genetics and the environment. Research has shown that skin pigmentation is regulated by the Melanocortin-1 Receptor gene (). In Japanese populations, Val92Met and Arg163Gln genotypes of gene polymorphisms are associated with freckles and lentigo solaris, because they have skin types II-III, but for Indonesians who are skin type IV, hyperpigmentation disorders are often melasma. This study aimed to identify the association between Val92Met and Arg163Gln genotypes of gene polymorphisms with the incidence of melasma in a Javanese women population. This study used unmatched case-control design, conducted by clinical examination and questionnaire. Data were analyzed with Chi-squared test and Odds Ratio (OR). This study evaluated 158 Javanese women from 18-60 years old with 79 case and 79 control subjects. The genotype of Val92Met was found more common in melasma subjects than in non-melasma (p0.005) with (OR2.53; 95% CI:1.21-5.29). By using a bivariate test we showed sun exposure and family history of melasma were risk factors for melasma (OR:1.99; 95% CI:1.04-3.78) and (OR:35.32; 95% CI:10.25-121.70). However, genotype of Arg163Gln was not a risk factor for the incidence of melasma (OR: 0.86; 95% CI:0.39-1.89). The findings showed Val92Met genotypes, sun exposure and family history were risk factors for melasma incidence. This is the first study on incidence of melasma in an Indonesian population and contributes to ongoing efforts to understand the mechanisms of melasma.
Chemical peeling for acne and melasma: current knowledge and innovations.
Conforti Claudio,Zalaudek Iris,Vezzoni Roberta,Retrosi Chiara,Fai Annatonia,Fadda Sara,Di Michele Eleonora,Dianzani Caterina
Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia
The skin is a dynamic organ that continuously eliminates an infinite number of keratinized cells through physiological mechanism. Chemical peeling is a widely used cosmetic procedure in medical practice. This technique consists of the application of one or more chemical ablative agents to the skin's surface in order to induce keratolysis or keratocoagulation. Exfoliation is followed by skin and epidermal regeneration from the adjacent epithelium and skin adnexa. Moreover, through an inflammatory reaction and the activation of the inflammation mediators, an increase in fibroblastic synthesis and in the production of new collagen and glycosaminoglycan fibers is induced. After the first treatment session, the appearance and the texture of the skin are significantly improved. Peeling agents may be divided into superﬁcial (epidermis-papillary dermis), medium-depth (papillary to upper reticular dermis) and deep subtypes based on the depth of their penetration (mid-reticular dermis). Superficial peel is mainly used for dyschromia, acne, post-inflammatory hyperpigmentation, melasma and actinic keratosis. Medium depth peel mainly treats solar keratosis or lentigines, pigmentary disorders and superficial scars. Skin photo-ageing, deep scars or wrinkles and precancerous skin lesions require a deep chemical peeling. The aim of this article is to review recent advances in chemical peel of melasma and acne.
Evaluation of ex vivo melanogenic response to UVB, UVA, and visible light in facial melasma and unaffected adjacent skin.
Alcantara Giovana Piteri,Esposito Ana Cláudia Cavalcante,Olivatti Thainá Oliveira Felicio,Yoshida Melissa Mari,Miot Hélio Amante
Anais brasileiros de dermatologia
BACKGROUND:The independent role of solar radiation in the differential melanogenesis between melasma and adjacent skin is unknown. OBJECTIVES:To assess the melanogenic responses of skin with facial melasma and of the adjacent skin to UVB, UVA, and visible light, in an ex vivo model. METHODS:This was a quasi-experimental study involving 22 patients with melasma. Facial melasma and adjacent skin samples were collected and stored in DMEM medium, at room temperature. One fragment was placed under the protection from light, while another was exposed to UVB, UVA, and visible light (blue-violet component): 166 mJ/cm, 1.524 J/cm, and 40 J/cm, respectively. Subsequently, all samples were kept for 72 hours in a dark environment and stained by Fontana-Masson to assess basal layer pigmentation, dendrites, and melanin granulation. RESULTS:Effective melanogenesis was observed in the basal layer in melasma and in the normal adjacent skin after all irradiations (p < 0.01), with the following median increment: UVB (4.7% vs. 8.5%), UVA (9.5% vs. 9.9%), and visible light (6.8% vs. 11.7%), with no significant difference between anatomical sites. An increase in melanin granulation (coarser melanosomes) was observed only after irradiation with UVA and only in the skin with melasma (p = 0.05). An increase in the melanocyte dendrite count induced by UVB radiation was observed in both anatomical sites (p ≤ 0.05). STUDY LIMITATIONS:Use of an ex vivo model, with independent irradiation regimes for UVB, UVA, and visible light. CONCLUSIONS:Melanogenesis induced by UVB, UVA, and visible light was observed both in melasma and in the adjacent skin. The morphological patterns suggest that different irradiations promote individualized responses on the skin with melasma.
Histopathological comparison of lesional and perilesional skin in melasma: A cross-sectional analysis.
Gautam Manjyot,Patil Sharmila,Nadkarni Nitin,Sandhu Manjit,Godse Kiran,Setia Maninder
Indian journal of dermatology, venereology and leprology
Background:Melasma is a common acquired hyperpigmentary disorder of the sun exposed skin, especially the face. The pathogenesis is unclear but interplay between genetic factors, hormones and ultraviolet radiation is important. We have evaluated the histological characteristics of melasma and compared the findings with adjacent normal skin. Methods:Skin biopsies were taken from both melasma and the surrounding perilesional normal skin in 50 Indian women. The sections were stained with hematoxylin and eosin, Fontana-Masson and Verhoeff-Van Gieson stains. Results:Biopsy from melasma showed significant epidermal atrophy, basal cell hyperpigmentation and solar elastosis when compared with the perilesional skin. We found that the proportion of pendulous melanocytes was significantly higher in the lesional biopsy compared with the perilesional biopsy (76% vs 42%, P < 0.001). Similarly, pigmentary incontinence and features of solar elastosis were significantly higher in the lesional skin compared with the perilesional skin. Conclusion:The characteristic histopathological features such as epidermal atrophy, basal cell hyperpigmentation and solar elastosis suggest the role of chronic sun exposure in the pathogenesis of melasma. Presence of pendulous melanocytes is a characteristic feature of melasma. The presence of pendulous melanocytes may have prognostic implications in melasma.
Topical metformin in the treatment of melasma: A preliminary clinical trial.
Banavase Channakeshavaiah Ravikumar,Andanooru Chandrappa Naveen Kumar
Journal of cosmetic dermatology
BACKGROUND:Melasma is a common acquired pigmentary disorder characterized by symmetric hyperpigmented macules on the face. Triple combination cream (TCC) remains the gold standard treatment but its prolonged use often causes adverse effects. Recently, studies have shown that topical metformin has melanopenic action. AIMS:To evaluate the safety and efficacy of topical metformin in the treatment of melasma and to compare its efficacy with TCC (hydroquinone 2% + tretinoin 0.025% + fluocinolone acetonide 0.01%). METHODS:This was a randomized controlled study conducted on 40 patients with melasma aged more than 18 years. Patients in group 1 (n = 20) were treated with 30% metformin lotion, whereas group 2 patients (n = 20) were treated with TCC for 8 weeks. Pigmentation was assessed using Melasma Area and Severity Index (MASI) at baseline and after 8 weeks. Outcome measures included global improvement scale (grades 1-4) and patient satisfaction. Safety was assessed according to adverse events and patch testing. RESULTS:All 40 patients completed the study. Out of 20 patients in group 1, 11 showed grade 1 improvement (1% to <25%) and grade 2 (25%-50%) and grade 3 (>50%-75%) improvements were seen in one patient each. In group 2, grades 1, 2, 3, and 4 improvements were seen in 14, 2, 1, and 1 patients, respectively. However, the difference was not statistically significant. Adverse events were noted in three patients in group 2 and none in group 1. CONCLUSION:Topical metformin is a novel, safe, and almost as effective modality as TCC to treat melasma.
Development and validation of a multidimensional questionnaire for evaluating quality of life in melasma (HRQ-melasma).
Pollo Camila Fernandes,Miot Luciane Donida Bartoli,Meneguin Silmara,Miot Hélio Amante
Anais brasileiros de dermatologia
BACKGROUND:Melasma has a major impact on quality of life. MELASQoL is the only validated specific psychometric instrument to evaluate melasma QoL. OBJECTIVE:To develop and validate a multidimensional questionnaire for evaluating quality of life related to facial melasma. METHODS:Cross-sectional study performed in 2 institutions (public and private) from Brazil. Two focus groups were carried out: 5 board-certified dermatologists and 10 melasma patients, indicating the dimensions and significant units of melasma QoL. The preliminary questionnaire with 49 itens was applied to 154 facial melasma patients. Item reduction was performed by Rasch analysis. Parallel evaluations of clinical (MASI), demographic, and QoL aspects (MELASQoL, DLQI) were performed. The dimensional structure was assessed by confirmatory factor analysis. Temporal stability was tested in a subgroup of 42 individuals within 7-14 days. RESULTS:The mean (SD) age of the 154 interviewed subjects was 39±8 years, and 87% were females. The median (p25-p75) DLQI and MELASQoL were: 2 (1-6) and 30 (17-44). HRQ-Melasma consisted of 19 items distributed in 4 dimensions: Physical/Appearance, Social/Professional, Psychological, and Treatment. Cronbach's alpha for HRQ-Melasma was 0.96, and >0.74 for each dimension. There was high correlation between HRQ-Melasma and DLQI and MELASQoL (rho=0.80 and 0.83), but modest with MASI (rho=0.35). Dimensional structure of HRQ-Melasma was stated by confirmatory factor analysis coefficients. Test-retest analysis disclosed an intraclass correlation coefficient of 0.91 (p<0.01). STUDY LIMITATIONS:Single-center study. CONCLUSIONS:A specific instrument to evaluate QoL in melasma with multidimensional characteristics was developed and validated, with appropriate psychometric performance.
Melasma, a photoaging disorder.
Passeron Thierry,Picardo Mauro
Pigment cell & melanoma research
Melasma is a common hyperpigmentary disorder. The impact on the quality of life of affected individuals is well demonstrated, demanding new therapeutic strategies. However, the treatment of melasma remains highly challenging. Melasma is often considered as the main consequence of female hormone stimulation on a predisposed genetic background. Although these two factors do contribute to this acquired pigmentary disorder, the last decade has revealed several other key players and brought new pieces to the complex puzzle of the pathophysiology of melasma. Here, we summarize the latest evidence on the pathophysiology of melasma, and we suggest that melasma might be a photoaging skin disorder affecting genetically predisposed individuals. Such data must be taken into consideration by clinicians as they could have a profound impact on the treatment and the prevention of melasma.
Ultrastructural characterization of damage in the basement membrane of facial melasma.
Espósito Ana Cláudia Cavalcante,Brianezi Gabrielli,de Souza Nathalia Pereira,Santos Daniela Carvalho,Miot Luciane Donida Bartoli,Miot Hélio Amante
Archives of dermatological research
The pathogenesis of melasma is not fully understood, and the role of skin basement membrane zone (BMZ) alterations in disease development and the maintenance of hypermelanogenesis are also poorly known. We performed a comparative study to characterize the ultrastructural alterations that occur in BMZ in melasma and adjacent normal skin, as well as we discuss the implications of these changes in the physiopathology of the disease. Pairs of facial skin biopsies (2 mm) from 10 women with melasma and normal skin (< 2 cm apart) were processed by Transmission Electronic Microscopy or immunohistochemistry for Melan-A counterstained with Periodic acid-Schiff stain. Cytoplasmic organelles (from keratinocyte or melanocyte), BMZ damage were assessed and melanocyte counting (total and pendulous) was done. There was greater amount of cytoplasmic organelles inside basal keratinocytes and melanocytes in melasma, as well as structural damaged areas in the lamina densa (disruptions, gaps, lower density and thinning) and anchoring fibrils (lamina lucida), compared to healthy adjacent skin. Areas with pendulous melanocytes are characterized by discontinuity of BMZ ultrastructure. The prominence of cytoplasmic organelles from melanocytes and keratinocytes evidences the involvement of both cell groups in melasma. The damage in the lamina densa and lamina lucida suggest the role of upper dermis injury/repair process in the pathogenesis of the disease.
Melasma and thyroid disorders: a systematic review and meta-analysis.
Kheradmand Motahhareh,Afshari Mahdi,Damiani Giovanni,Abediankenari Saeid,Moosazadeh Mahmood
International journal of dermatology
BACKGROUND:Thyroid hormones may play a key role in melasma; however, melasma link with thyroid disorders remains controversial. OBJECTIVES:To compare the serum levels of thyroid-stimulating hormone (TSH), T4, T3, anti-thyroid peroxidase (anti-TPO), and antithyroglobulin between patients with melasma and control group using meta-analysis. METHODS:We screened 10 databanks and search engines, searched mesh and nonmesh terms. The identified evidences were reviewed and quality assessed using the Newcastle-Ottawa Scale (NOS). The heterogeneity between the primary results was investigated using Cochrane and I-square indices. Random effect model was applied to combine the standardized mean differences of thyroid function indicators between patients with and without melasma. P values meta-analysis was used to investigate the association between anti-TPO and melasma. RESULTS:We included seven studies, 473 cases, and 379 controls that had been investigated. The total standardized mean differences (95% confidence intervals) of TSH, T3, T4, and antithyroglobulin antibody between cases and controls were estimated to be 0.33 (0.18, 0.47), -0.01 (-0.20, 0.19), -1.50 (-2.96, -0.04), and 0.62 (0.14, 1.11), respectively. The corresponding figures among women were 0.35 (0.17, 0.52), 0.10 (-0.17, 0.38), -2.75 (-6.30, 0.81), and 0.99 (0.14, 1.83), respectively. P value of meta-analysis showed a significant relationship between anti-TPO serum level and melasma (Fisher = 26.80, P = 0.020). CONCLUSION:Serum levels of TSH, anti-TPO, and antithyroglobulin antibody were significantly higher in patients with melasma than those without melasma. Moreover, these differences were more severe among women with melasma.
Melatonin and oxidative stress in melasma - an unexplored territory; a prospective study.
Sarkar Rashmi,Devadasan Shanthy,Choubey Vikrant,Goswami Binita
International journal of dermatology
BACKGROUND:Melasma, an acquired disorder of hyperpigmentation, is the most common pigmentary disorder in India. Many factors are implicated in the pathogenesis, and recently the role of oxidative damage including melatonin has been postulated. This study was undertaken to evaluate the role of oxidative stress and serum melatonin in pathogenesis of melasma. METHODS:Seventy-five patients with melasma and an equal number of age and sex-matched controls were included in the study. Clinical characteristics were noted, and baseline severity assessment using modified Melasma Area and Severity Index (MASI) was done in all patients. Serum melatonin, catalase, protein carbonyl, and nitric oxide levels were measured and compared between cases and controls. RESULTS:The serum levels of melatonin and catalase were significantly lower among the cases as compared to controls, while the serum levels of protein carbonyl and nitric oxide were significantly higher in cases compared to controls. There was no statistically significant correlation between these markers of oxidative stress and severity of the disease. CONCLUSIONS:Oxidative stress is increased in patients with melasma compared to the control group in this study. A state of melatonin deficit also exists in patients with melasma. No correlation between the oxidative stress and severity of the disease was found. Further and larger studies including therapeutic trials with powerful antioxidants are warranted.
Melasma: How hormones can modulate skin pigmentation.
Filoni Angela,Mariano Maria,Cameli Norma
Journal of cosmetic dermatology
We described-along with a genetic predisposition and exposure to sunlight, as the main factors for melasma development-pregnancy, hormonal therapies, and oral contraceptive pills. Whilst hormonal alteration or therapies are frequently reported in literature in association with melasma, studies analyzing the laboratoristic correlation are limited. We review data published on hormones variations both in women and males with melasma and report some peculiar clinical cases that further demonstrate how the relationship between hormone secretion and melasma development is difficult to be defined.
In vivo multiphoton microscopy of melasma.
Lentsch Griffin,Balu Mihaela,Williams Joshua,Lee Sanghoon,Harris Ronald M,König Karsten,Ganesan Anand,Tromberg Bruce J,Nair Nirmala,Santhanam Uma,Misra Manoj
Pigment cell & melanoma research
Melasma is a skin disorder characterized by hyperpigmented patches due to increased melanin production and deposition. In this pilot study, we evaluate the potential of multiphoton microscopy (MPM) to characterize non-invasively the melanin content, location, and distribution in melasma and assess the elastosis severity. We employed a clinical MPM tomograph to image in vivo morphological features in melasma lesions and adjacent normal skin in 12 patients. We imaged dermal melanophages in most dermal melasma lesions and occasionally in epidermal melasma. The melanin volume fraction values measured in epidermal melasma (14% ± 4%) were significantly higher (p < 0.05) than the values measured in perilesional skin (11% ± 3%). The basal keratinocytes of melasma and perilesions showed different melanin distribution. Elastosis was predominantly more severe in lesions than in perilesions and was associated with changes in melanin distribution of the basal keratinocytes. These results demonstrate that MPM may be a non-invasive imaging tool for characterizing melasma.
Melasma Treatment: An Evidence-Based Review.
McKesey Jacqueline,Tovar-Garza Andrea,Pandya Amit G
American journal of clinical dermatology
BACKGROUND:Melasma is an acquired, chronic pigmentary disorder predominantly affecting women. It may significantly affect quality of life and self-esteem due to its disfiguring appearance. Multiple treatments for melasma are available, with mixed results. OBJECTIVE:The aim of this article was to conduct an evidence-based review of all available interventions for melasma. METHODS:A systematic literature search of the PubMed electronic database was performed using the keywords 'melasma' and/or 'chloasma' in the title, through October 2018. The search was then limited to 'randomized controlled trial' and 'controlled clinical trial' in English-language journals. The Cochrane database was also searched for systematic reviews. RESULTS:The electronic search yielded a total of 212 citations. Overall, 113 studies met the inclusion criteria and were included in this review, with a total of 6897 participants. Interventions included topical agents, chemical peels, laser- and light-based devices, and oral agents. Triple combination cream (hydroquinone, tretinoin, and corticosteroid) remains the most effective treatment for melasma, as well as hydroquinone alone. Chemical peels and laser- and light-based devices have mixed results. Oral tranexamic acid is a promising new treatment for moderate and severe recurrent melasma. Adverse events from all treatments tend to be mild, and mainly consist of skin irritation, dryness, burning, erythema, and post-inflammatory hyperpigmentation. CONCLUSIONS:Hydroquinone monotherapy and triple combination cream are the most effective and well-studied treatments for melasma, whereas chemical peels and laser- and light-based therapies are equal or inferior to topicals, but offer a higher risk of adverse effects. Oral tranexamic acid may be a safe, systemic adjunctive treatment for melasma, but more studies are needed to determine its long-term safety and efficacy. Limitations of the current evidence are heterogeneity of study design, small sample size, and lack of long-term follow-up, highlighting the need for larger, more rigorous studies in the treatment of this recalcitrant disorder.
A comparison of serum zinc levels in melasma and non-melasma patients: a preliminary study of thyroid dysfunction.
Sastrini Sekarnesia Indina,Sitohang Irma Bernadette S,Agustin Triana,Wisnu Wismandari,Hoemardani Aida S D
Acta dermatovenerologica Alpina, Pannonica, et Adriatica
INTRODUCTION:Melasma is an acquired hyperpigmentation disorder, clinically identified by symmetrical blackish-brown macules, especially on the facial area. Several factors are thought to play a role, including thyroid dysfunction and zinc deficiency. The aim of this study was to determine serum zinc levels in melasma and non-melasma patients with and without thyroid dysfunction. METHODS:A cross-sectional study was conducted in Jakarta in September 2019. There were 60 melasma patients and 60 non-melasma patients. The two groups were matched for age and sex. Atomic absorption spectrophotometry was used to measure serum zinc levels. Blood laboratory tests were used to check thyroid function by measuring thyroid stimulating hormone and free T4. Statistical analysis was performed using SPSS software. RESULTS:The mean serum zinc level in the melasma group was 10.25 ± 1.89 μmol/l and in the non-melasma group 10.29 ± 1.46 μmol/l (< 0.901). The mean serum zinc level in melasma patients with thyroid dysfunction was 8.77 ± 0.69 μmol/l, in melasma patients without thyroid dysfunction 10.33 ± 1.89 μmol/l, in non-melasma patients with thyroid dysfunction 10.48 ± 2.4 μmol/l, and in non-melasma patients without thyroid dysfunction 10.27 ± 1.4 μmol/l (< 0.184). CONCLUSIONS:There was no significant difference between serum zinc levels in the melasma and non-melasma groups with and without thyroid dysfunction.
Effect of oral tranexamic acid on erythema index in patients with melasma.
Nguyen Jennifer,Rajgopal Bala Harini,Ross Angelique,Wong Celestine C,Paul Eldho,Rodrigues Michelle
The Australasian journal of dermatology
Melasma is a common disorder of hyperpigmentation that presents a therapeutic challenge for clinical dermatologists. The pathogenesis is complex, but previous studies have demonstrated vascular proliferation is a key factor in the development of the classic hyperpigmented patches. Studies have revealed reduction of erythema by oral tranexamic acid; however, there has been no direct comparison to placebo. This 24-week randomised placebo-controlled trial demonstrates oral tranexamic acid may improve erythema in melasma. This mechanism of action may be the reason for the success of tranexamic acid in complex and difficult to treat melasma.
Senescent fibroblasts in melasma pathophysiology.
Kim Misun,Kim So Min,Kwon Soohyun,Park Tae Jun,Kang Hee Young
It has been proposed that melasma is a photoageing skin disorder. The photoaged fibroblasts have been suggested as an important source of melanogenic factors which are involved in the regulation of pigmentation. To investigate whether melasma includes senescent cells, lesional and perilesional normal skin from 38 melasma patients was assessed using a cell senescence marker, p16 . The results showed that lesional dermal skin had more p16 -positive senescent cells than perilesional skin. The impact of senescent fibroblasts was further investigated in a pilot study using radiofrequency (RF) intervention for melasma. It showed that the RF therapy decreased the number of senescent cells with increased expression of procollagen-1, which were associated with reduced epidermal pigmentation. This leads us to the speculation that senescent fibroblasts may contribute to drive melasma and might be considered as a potential therapeutic target.
Future therapies in melasma: What lies ahead?
Sarkar Rashmi,Bansal Anuva,Ailawadi Pallavi
Indian journal of dermatology, venereology and leprology
Melasma is a common, acquired, symmetrical hypermelanosis. It negatively impacts the patient's quality of life and responds poorly to treatment. Although earlier classified as epidermal and dermal, melasma is now thought to be a complex interaction between epidermal melanocytes, keratinocytes, dermal fibroblasts, mast cells, and vascular endothelial cells. Factors influencing melasma may include inflammation, reactive oxygen species, ultraviolet radiation, genetic factors, and hormones. With a better understanding of the pathogenesis of melasma and the realization that targeting melanin synthesis alone is not very effective, treatments focussing on newly implicated factors have been developed. These include agents targeting hyperactive melanocytes, melanosomal transfer to keratinocytes, defective skin barrier, the mast cells, vasculature, and estrogen receptors as well as drugs with anti-inflammatory and antioxidant activity. Many of these newer agents are botanicals with multimodal mechanisms of action that offer a better safety profile when compared with the conventional drugs. There has also been a focus on oral agents such as tranexamic acid, flutamide, and ascorbic acid. It has been suggested that the "triple therapy of the future" may be a combination of hydroquinone, an antiestrogen and a vascular endothelial growth factor inhibitor, as the "ideal" skin-lightening agent.
An Herbal H2 Blocker in Melasma Treatment.
Mahjour Marjan,Khoushabi Arash
Current drug discovery technologies
BACKGROUND:Melasma is a skin pigmentation disorder that remains resistant to available therapies. The exact cause of melasma is unknown. Histamine is an inflammatory factor. Its involvement in pigmentation is obscure. The aim of this study is to introduce an herbal antihistamine H2 receptor which is effective in these disorders. METHODS:This is a review study by searching the electronic databases and also Persian Medicine books, from 2000 to 2018 by the keywords such as H2 antagonist, H2 blocker and melasma. RESULTS:According to the researched studies, histamine can induce melanogenesis and melasma after a series of stages in the body. Also, Histamine, through receptors 2, triggers melasma. Therefore, it can be said that antihistamine H2 receptor can be effective in melasma. Considering chemical antihistamine, H2 receptors have side effects, such as digestive problems, H2 antagonists can be used in the treatment of diseases such as dyspepsia but they have multiple complications. On the other hand, there is an herbal H2 antagonist that can be useful for melasma due to having some special properties. CONCLUSION:Herbal H2 blockers should be noted in melasma treatment along with the topical drugs.
Melasma: Updates and perspectives.
Kwon Soon-Hyo,Na Jung-Im,Choi Ji-Young,Park Kyoung-Chan
Management of melasma is highly challenging due to inconsistent treatment results and frequent relapses. However, recent studies revealed that melasma may not only be a disease of melanocytes, but also a photoaging skin disorder. Herein, we attempt to validate that melasma is indeed a photoaging disorder by presenting the histopathologic findings of melasma: solar elastosis, altered basement membrane, increased vascularization and increased mast cell count. We also provide some therapeutic implications based on these findings and a discussion on the latest updates and perspectives regarding treatment.