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15 pages, 4158 KiB

Open AccessArticle

Upregulated Guanine Deaminase Is Involved in Hyperpigmentation of Seborrheic Keratosis via Uric Acid Release

by Kyung Ah Cheong, In Sup Kil, Hyuk Wan Ko and Ai-Young Lee

Int. J. Mol. Sci. 2021, 22(22), 12501; https://doi.org/10.3390/ijms222212501 - 19 Nov 2021

Cited by 5 | Viewed by 2480

Abstract

Seborrheic keratosis, which is a benign tumor composed of epidermal keratinocytes, develops common in the elderly. Uric acid generated by upregulated guanine deaminase (GDA) has been identified to cause UV-induced keratinocyte senescence in seborrheic keratosis. Seborrheic keratosis is also frequently pigmented. [...] Read more.

Seborrheic keratosis, which is a benign tumor composed of epidermal keratinocytes, develops common in the elderly. Uric acid generated by upregulated guanine deaminase (GDA) has been identified to cause UV-induced keratinocyte senescence in seborrheic keratosis. Seborrheic keratosis is also frequently pigmented. Growing evidences indicate that hyperuricemia is a risk factor of acanthosis nigricans, an acquired skin hyperpigmentation. The objective of this study was to investigate role of GDA and its metabolic end product, uric acid, in hyperpigmentation of patients with seborrheic keratosis using their lesional and non-lesional skin specimen sets and cultured primary human epidermal keratinocytes with or without GDA overexpression or uric acid treatment. GDA-overexpressing keratinocytes or their conditioned media containing uric acid increased expression levels of MITF and tyrosinase in melanocytes. Uric acid released from keratinocytes was facilitated by ABCG2 transporter with the help of PDZK1 interaction. Released uric acid was taken by URAT1 transporter in melanocytes, stimulating melanogenesis through p38 MAPK activation. Overall, GDA upregulation in seborrheic keratosis plays a role in melanogenesis via its metabolic end product uric acid, suggesting that seborrheic keratosis as an example of hyperpigmentation associated with photoaging. Full article

(This article belongs to the Special Issue Etio-Pathogenesis and Therapeutic Approaches of Skin Pigmentation Abnormalities)

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13 pages, 5956 KiB

Open AccessArticle

Cathepsin L, a Target of Hypoxia-Inducible Factor-1-α, Is Involved in Melanosome Degradation in Melanocytes

by Ji Young Kim, Eun Jung Lee, Yuri Ahn, Sujin Park, Yu Jeong Bae, Tae Gyun Kim and Sang Ho Oh

Int. J. Mol. Sci. 2021, 22(16), 8596; https://doi.org/10.3390/ijms22168596 - 10 Aug 2021

Cited by 8 | Viewed by 2877

Abstract

Hypoxic conditions induce the activation of hypoxia-inducible factor-1α (HIF-1α) to restore the supply of oxygen to tissues and cells. Activated HIF-1α translocates into the nucleus and binds to hypoxia response elements to promote the transcription of target genes. Cathepsin L (CTSL) is a [...] Read more.

Hypoxic conditions induce the activation of hypoxia-inducible factor-1α (HIF-1α) to restore the supply of oxygen to tissues and cells. Activated HIF-1α translocates into the nucleus and binds to hypoxia response elements to promote the transcription of target genes. Cathepsin L (CTSL) is a lysosomal protease that degrades cellular proteins via the endolysosomal pathway. In this study, we attempted to determine if CTSL is a hypoxia responsive target gene of HIF-1α, and decipher its role in melanocytes in association with the autophagic pathway. The results of our luciferase reporter assay showed that the expression of CTSL is transcriptionally activated through the binding of HIF1-α at its promoter. Under autophagy-inducing starvation conditions, HIF-1α and CTSL expression is highly upregulated in melan-a cells. The mature form of CTSL is closely involved in melanosome degradation through lysosomal activity upon autophagosome–lysosome fusion. The inhibition of conversion of pro-CTSL to mature CTSL leads to the accumulation of gp100 and tyrosinase in addition to microtubule-associated protein 1 light chain 3 (LC3) II, due to decreased lysosomal activity in the autophagic pathway. In conclusion, we have identified that CTSL, a novel target of HIF-1α, participates in melanosome degradation in melanocytes through lysosomal activity during autophagosome–lysosome fusion. Full article

(This article belongs to the Special Issue Etio-Pathogenesis and Therapeutic Approaches of Skin Pigmentation Abnormalities)

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Review

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14 pages, 704 KiB

Open AccessReview

Role of Cytokines in Vitiligo: Pathogenesis and Possible Targets for Old and New Treatments

by Paolo Custurone, Luca Di Bartolomeo, Natasha Irrera, Francesco Borgia, Domenica Altavilla, Alessandra Bitto, Giovanni Pallio, Francesco Squadrito and Mario Vaccaro

Int. J. Mol. Sci. 2021, 22(21), 11429; https://doi.org/10.3390/ijms222111429 - 22 Oct 2021

Cited by 28 | Viewed by 6826

Abstract

Vitiligo is a chronic autoimmune dermatosis of which the pathogenesis remains scarcely known. A wide variety of clinical studies have been proposed to investigate the immune mediators which have shown the most recurrency. However, such trials have produced controversial results. The aim of [...] Read more.

Vitiligo is a chronic autoimmune dermatosis of which the pathogenesis remains scarcely known. A wide variety of clinical studies have been proposed to investigate the immune mediators which have shown the most recurrency. However, such trials have produced controversial results. The aim of this review is to summarize the main factors involved in the pathogenesis of vitiligo, the latest findings regarding the cytokines involved and to evaluate the treatments based on the use of biological drugs in order to stop disease progression and achieve repigmentation. According to the results, the most recurrent studies dealt with inhibitors of IFN-gamma and TNF-alpha. It is possible that, given the great deal of cytokines involved in the lesion formation process of vitiligo, other biologics could be developed in the future to be used as adjuvants and/or to entirely replace the treatments that have proven to be unsatisfactory so far. Full article

(This article belongs to the Special Issue Etio-Pathogenesis and Therapeutic Approaches of Skin Pigmentation Abnormalities)

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11 pages, 1116 KiB

Open AccessReview

Metabolic Comorbidities in Vitiligo: A Brief Review and Report of New Data from a Single-Center Experience

by Andrea D’Arino, Mauro Picardo, Mauro Truglio, Alessia Pacifico and Paolo Iacovelli

Int. J. Mol. Sci. 2021, 22(16), 8820; https://doi.org/10.3390/ijms22168820 - 17 Aug 2021

Cited by 9 | Viewed by 4867

Abstract

Among disorders of pigmentation, vitiligo is the most common, with an estimated prevalence between 0.5% and 1%. The disease has gathered increased attention in the most recent years, leading to a better understanding of the disease’s pathophysiology and its implications and to the [...] Read more.

Among disorders of pigmentation, vitiligo is the most common, with an estimated prevalence between 0.5% and 1%. The disease has gathered increased attention in the most recent years, leading to a better understanding of the disease’s pathophysiology and its implications and to the development of newer therapeutic strategies. A better, more integrated approach is already in use for other chronic inflammatory dermatological diseases such as psoriasis, for which metabolic comorbidities are well-established and part of the routine clinical evaluation. The pathogenesis of these might be linked to cytokines which also play a role in vitiligo pathogenesis, such as IL-1, IL-6, TNF-α, and possibly IL-17. Following the reports of intrinsic metabolic alterations reported by our group, in this brief review, we analyze the available data on metabolic comorbidities in vitiligo, accompanied by our single-center experience. Increased awareness of the metabolic aspects of vitiligo is crucial to improving patient care. Full article

(This article belongs to the Special Issue Etio-Pathogenesis and Therapeutic Approaches of Skin Pigmentation Abnormalities)

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28 pages, 3413 KiB

Open AccessReview

Role of Amine Neurotransmitters and Their Receptors in Skin Pigmentation: Therapeutic Implication

by Enkhmend Enkhtaivan and Chang Hoon Lee

Int. J. Mol. Sci. 2021, 22(15), 8071; https://doi.org/10.3390/ijms22158071 - 28 Jul 2021

Cited by 18 | Viewed by 5051

Abstract

Skin pigmentation can occur due to increased melanin, including melanocyte proliferation, melanin biosynthesis, or melanocyte migration. There are many factors that influence the melanin production process, but the role of neurotransmitters in this process is still unclear. We found that histamine and serotonin [...] Read more.

Skin pigmentation can occur due to increased melanin, including melanocyte proliferation, melanin biosynthesis, or melanocyte migration. There are many factors that influence the melanin production process, but the role of neurotransmitters in this process is still unclear. We found that histamine and serotonin influence the different stages of melanogenesis and melanogenesis, which increase melanogenesis. Since then, several related papers have been published, and from these papers, it has been recognised that the role of neurotransmitters in skin-pigment-related diseases needs to be summarised. By introducing the role of neurotransmitters in the regulation of various pigment disorders, including vitiligo and melasma, through this review, many researchers can be expected to try to apply neurotransmitter-related agonists and antagonists as treatments for skin pigment disorders. Full article

(This article belongs to the Special Issue Etio-Pathogenesis and Therapeutic Approaches of Skin Pigmentation Abnormalities)

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12 pages, 276 KiB

Open AccessReview

Anti-Pigmentary Natural Compounds and Their Mode of Action

by Kyuri Kim, YoonJung Huh and Kyung-Min Lim

Int. J. Mol. Sci. 2021, 22(12), 6206; https://doi.org/10.3390/ijms22126206 - 8 Jun 2021

Cited by 26 | Viewed by 3762

Abstract

Hyper-activated melanocytes are the major cause of skin hyper-pigmentary disorders, such as freckles and melasma. Increasing efforts have been made to search for materials with depigmenting activity to develop functional cosmetics. As a result, numerous materials have been reported to have depigmenting activity [...] Read more.

Hyper-activated melanocytes are the major cause of skin hyper-pigmentary disorders, such as freckles and melasma. Increasing efforts have been made to search for materials with depigmenting activity to develop functional cosmetics. As a result, numerous materials have been reported to have depigmenting activity but some of them are known to cause unwanted side effects. Consequently, anti-pigmentary natural compounds without concern of toxicity are in great demand. Virtually all sorts of natural sources have been investigated to find anti-pigmentary natural compounds. This review summarizes recently reported anti-pigmentary natural compounds and their mode of action from the ocean, plants, and bacteria. Full article

(This article belongs to the Special Issue Etio-Pathogenesis and Therapeutic Approaches of Skin Pigmentation Abnormalities)

13 pages, 2472 KiB

Open AccessReview

Development of Pigmentation-Regulating Agents by Drug Repositioning

by Seo-Mi-Gon Jeong and Tae-Jin Yoon

Int. J. Mol. Sci. 2021, 22(8), 3894; https://doi.org/10.3390/ijms22083894 - 9 Apr 2021

Cited by 14 | Viewed by 4439

Abstract

Skin color is determined by the processes of melanin synthesis and distribution. Problems in various molecules or signaling pathways involved in melanin synthesis contribute to skin pigmentation defects. Several trials have been conducted on the production of pigmentation-regulating agents, and drug repositioning has [...] Read more.

Skin color is determined by the processes of melanin synthesis and distribution. Problems in various molecules or signaling pathways involved in melanin synthesis contribute to skin pigmentation defects. Several trials have been conducted on the production of pigmentation-regulating agents, and drug repositioning has emerged as a modern technique to identify new uses for existing drugs. Our research team has researched substances or drugs associated with pigmentation control and, as a result, nilotinib, sorafenib, and ICG-001 have been found to promote pigmentation, while 5-iodotubercidin inhibits pigmentation. Therefore, these substances or medications were suggested as potential therapeutics for pigmentation disorders by drug repositioning. Full article

(This article belongs to the Special Issue Etio-Pathogenesis and Therapeutic Approaches of Skin Pigmentation Abnormalities)

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19 pages, 984 KiB

Open AccessReview

Skin Pigmentation Abnormalities and Their Possible Relationship with Skin Aging

by Ai-Young Lee

Int. J. Mol. Sci. 2021, 22(7), 3727; https://doi.org/10.3390/ijms22073727 - 2 Apr 2021

Cited by 45 | Viewed by 7084

Abstract

Skin disorders showing abnormal pigmentation are often difficult to manage because of their uncertain etiology or pathogenesis. Abnormal pigmentation is a common symptom accompanying aging skin. The association between skin aging and skin pigmentation abnormalities can be attributed to certain inherited disorders characterized [...] Read more.

Skin disorders showing abnormal pigmentation are often difficult to manage because of their uncertain etiology or pathogenesis. Abnormal pigmentation is a common symptom accompanying aging skin. The association between skin aging and skin pigmentation abnormalities can be attributed to certain inherited disorders characterized by premature aging and abnormal pigmentation in the skin and some therapeutic modalities effective for both. Several molecular mechanisms, including oxidative stress, mitochondrial DNA mutations, DNA damage, telomere shortening, hormonal changes, and autophagy impairment, have been identified as involved in skin aging. Although each of these skin aging-related mechanisms are interconnected, this review examined the role of each mechanism in skin hyperpigmentation or hypopigmentation to propose the possible association between skin aging and pigmentation abnormalities. Full article

(This article belongs to the Special Issue Etio-Pathogenesis and Therapeutic Approaches of Skin Pigmentation Abnormalities)

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12 pages, 791 KiB

Open AccessReview

Glyoxalase System in the Progression of Skin Aging and Skin Malignancies

by Silvia Yumnam, Lalita Subedi and Sun Yeou Kim

Int. J. Mol. Sci. 2021, 22(1), 310; https://doi.org/10.3390/ijms22010310 - 30 Dec 2020

Cited by 26 | Viewed by 3846

Abstract

Dicarbonyl compounds, including methylglyoxal (MGO) and glyoxal (GO), are mainly formed as byproducts of glucose metabolism. The main glyoxalase system consists of glyoxalase I and II (Glo1 and Glo2) and is the main enzyme involved in the detoxification of dicarbonyl stress, which occurs [...] Read more.

Dicarbonyl compounds, including methylglyoxal (MGO) and glyoxal (GO), are mainly formed as byproducts of glucose metabolism. The main glyoxalase system consists of glyoxalase I and II (Glo1 and Glo2) and is the main enzyme involved in the detoxification of dicarbonyl stress, which occurs as an accumulation of MGO or GO due to decreased activity or expression of Glo1. Dicarbonyl stress is a major cause of cellular and tissue dysfunction that causes various health issues, including diabetes, aging, and cancer. The skin is the largest organ in the body. In this review, we discuss the role of the glyoxalase system in the progression of skin aging, and more importantly, skin malignancies. We also discuss the future prospects of the glyoxalase system in other skin abnormalities such as psoriasis and vitiligo, including hyperpigmentation. Finally, in the present review, we suggest the role of glyoxalase in the progression of skin aging and glyoxalase system as a potential target for anticancer drug development for skin cancer. Full article

(This article belongs to the Special Issue Etio-Pathogenesis and Therapeutic Approaches of Skin Pigmentation Abnormalities)

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