scholarly journals Mammalian pigmentation is regulated by a distinct cAMP-dependent mechanism that controls melanosome pH

2018 ◽  
Vol 11 (555) ◽  
pp. eaau7987 ◽  
Author(s):  
Dalee Zhou ◽  
Koji Ota ◽  
Charlee Nardin ◽  
Michelle Feldman ◽  
Adam Widman ◽  
...  
Keyword(s):  
Skin Cancer ◽  
Skin Color ◽  
Skin Pigmentation ◽  
Melanin Production ◽  
Melanocortin 1 Receptor ◽  
New Class ◽  
Camp Pathway ◽  
Human Melanocytes ◽  
Rate Limiting

The production of melanin increases skin pigmentation and reduces the risk of skin cancer. Melanin production depends on the pH of melanosomes, which are more acidic in lighter-skinned than in darker-skinned people. We showed that inhibition of soluble adenylyl cyclase (sAC) controlled pigmentation by increasing the pH of melanosomes both in cells and in vivo. Distinct from the canonical melanocortin 1 receptor (MC1R)–dependent cAMP pathway that controls pigmentation by altering gene expression, we found that inhibition of sAC increased pigmentation by increasing the activity of tyrosinase, the rate-limiting enzyme in melanin synthesis, which is more active at basic pH. We demonstrated that the effect of sAC activity on pH and melanin production in human melanocytes depended on the skin color of the donor. Last, we identified sAC inhibitors as a new class of drugs that increase melanosome pH and pigmentation in vivo, suggesting that pharmacologic inhibition of this pathway may affect skin cancer risk or pigmentation conditions.

scholarly journals Molecular Mechanisms of Anti-Melanogenic Gedunin Derived from Neem Tree (Azadirachta indica) Using B16F10 Mouse Melanoma Cells and Early-Stage Zebrafish

Plants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 330
Author(s):  
Hwang-Ju Jeon ◽  
Kyeongnam Kim ◽  
Chaeeun Kim ◽  
Myoung-Jin Kim ◽  
Tae-Oh Kim ◽  
...  
Keyword(s):  
Skin Color ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Melanoma Cells ◽  
Ultraviolet Rays ◽  
Melanin Production ◽  
Zebrafish Model ◽  
Mouse Melanoma

Melanogenesis represents a series of processes that produce melanin, a protective skin pigment (against ultraviolet rays), and determines human skin color. Chemicals reducing melanin production have always been in demand in the cosmetic market because of skincare interests, such as whitening. The main mechanism for inhibiting melanin production is the inhibition of tyrosinase (TYR), a key enzyme for melanogenesis. Here, we evaluated gedunin (Ged), a representative limonoid, for its anti-melanogenesis action. Melanin production in vitro was stimulated by alpha-melanocyte stimulating hormone (α-MSH) in B16F10 mouse melanoma cells. Ged reduced α-MSH-stimulated melanin production, inhibiting TYR activity and protein amount. We confirmed this result in vivo in a zebrafish model for melanogenesis. There was no sign of toxicity and malformation of zebrafish embryos during development in all treated concentrations. Ged reduced the number of produced zebrafish embryo pigment dots and melanin contents of embryos. The highly active concentration of Ged (100 µM) was much lower than the positive control, kojic acid (8 mM). Hence, Ged could be a fascinating candidate for anti-melanogenesis reagents.

ACTH STIMULATES MELANOGENESIS IN CULTURED HUMAN MELANOCYTES

1994 ◽  
Vol 140 (1) ◽  
pp. R1-R3 ◽  
Author(s):  
G. Hunt ◽  
C. Todd ◽  
S. Kyne ◽  
A.J. Thody
Keyword(s):  
Dose Response ◽  
Plasma Levels ◽  
Culture System ◽  
Skin Pigmentation ◽  
Physiological Role ◽  
Melanin Content ◽  
Response Curves ◽  
Human Melanocytes ◽  
First Time ◽  
Rate Limiting

ABSTRACT While ACTH is known to induce skin pigmentation in man, its effects on cultured human melanocytes have not been investigated. Using a culture system free of artificial mitogens, we report for the first time that ACTH stimulates melanogenesis in cultured human melanocytes. While ACTH, α-MSH and the synthetic α-MSH analogue Nle4DPhe7α-MSH all stimulate the activity of tyrosinase, the rate limiting enzyme in melanogenesis, and all produce a 50% increase in the melanin content of the cells at a concentration of 10−8-10−7 mol/l, the shapes of the dose response curves differ: those for the MSH peptides are sigmoidal while those for ACTH are biphasic. In addition, human melanocytes are able to respond to concentrations of ACTH comparable with physiological plasma levels. We suggest that ACTH may be relatively more important than α-MSH as a pigmentary hormone in man and could have a physiological role in skin pigmentation.

Rate Limiting Factors in Melanocortin 1 Receptor Signalling Throughthe cAMP Pathway

2003 ◽  
Vol 16 (5) ◽  
pp. 540-547 ◽  
Author(s):  
JesÚs SÁnchez MÁs ◽  
Ineke Gerritsen ◽  
Christa Hahmann ◽  
Celia JimÉnez-Cervantes ◽  
JosÉ Carlos García-BorrÓn
Keyword(s):  
Limiting Factors ◽  
Melanocortin 1 Receptor ◽  
Receptor Signalling ◽  
Camp Pathway ◽  
Rate Limiting

scholarly journals MC1R: Front and Center in the Bright Side of Dark Eumelanin and DNA Repair

2018 ◽  
Vol 19 (9) ◽  
pp. 2667 ◽  
Author(s):  
Viki Swope ◽  
Zalfa Abdel-Malek
Keyword(s):  
Dna Repair ◽  
Skin Cancer ◽  
Skin Color ◽  
Skin Pigmentation ◽  
Hair Color ◽  
Protective Mechanism ◽  
Solar Ultraviolet Radiation ◽  
Paracrine Factors ◽  
Repair Capacity ◽  
Solar Uv

Melanin, the pigment produced by specialized cells, melanocytes, is responsible for skin and hair color. Skin pigmentation is an important protective mechanism against the DNA damaging and mutagenic effects of solar ultraviolet radiation (UV). It is acknowledged that exposure to UV is the main etiological environmental factor for all forms of skin cancer, including melanoma. DNA repair capacity is another major factor that determines the risk for skin cancer. Human melanocytes synthesize eumelanin, the dark brown form of melanin, as well as pheomelanin, which is reddish-yellow in color. The relative rates of eumelanin and pheomelanin synthesis by melanocytes determine skin color and the sensitivity of skin to the drastic effects of solar UV. Understanding the complex regulation of melanocyte function and how it responds to solar UV has a huge impact on developing novel photoprotective strategies to prevent skin cancer, particularly melanoma, the most fatal form, which originates from melanocytes. This review provides an overview of the known differences in the photoprotective effects of eumelanin versus pheomelanin, how these two forms of melanin are regulated genetically and biochemically, and their impact on the DNA damaging effects of UV exposure. Additionally, this review briefly discusses the role of paracrine factors, focusing on α-melanocortin (α-melanocyte stimulating hormone; α-MSH), in regulating melanogenesis and the response of melanocytes to UV, and describes a chemoprevention strategy based on targeting the melanocortin 1 receptor (MC1R) by analogs of its physiological agonist α-MSH.

scholarly journals The human non-visual opsin OPN3 regulates pigmentation of epidermal melanocytes through interaction with MC1R

2019 ◽  
Author(s):  
Rana N. Ozdeslik ◽  
Lauren E. Olinski ◽  
Melissa M. Trieu ◽  
Daniel D. Oprian ◽  
Elena Oancea
Keyword(s):  
Light Sensitivity ◽  
G Protein Coupled Receptors ◽  
Negative Regulator ◽  
Melanin Production ◽  
Melanocortin 1 Receptor ◽  
Skin Cells ◽  
Skin Physiology ◽  
Human Melanocytes ◽  
G Protein Coupled ◽  
The Brain

AbstractOpsins form a family of light-activated, retinal-dependent G-protein coupled receptors (GPCRs) that serve a multitude of visual and non-visual functions. Opsin3 (OPN3 or encephalopsin), initially identified in the brain, remains one of the few members of the mammalian opsin family with unknown function and ambiguous light-absorption properties. We recently discovered that OPN3 is highly expressed in human epidermal melanocytes—the skin cells that produce melanin. The melanin pigment is a critical defense against ultraviolet radiation and its production is mediated by the Gαs-coupled melanocortin-1 receptor (MC1R). The physiological function and light-sensitivity of OPN3 in melanocytes is yet to be determined. Here we show that in human epidermal melanocytes OPN3 acts as a negative regulator of melanin production by interacting with MC1R and modulating its cAMP signaling. OPN3 negatively regulates the cAMP response evoked by MC1R via activation of the Gαi subunit of G-proteins, thus decreasing cellular melanin levels. In addition to their functional relationship, OPN3 and MC1R colocalize at both the plasma membrane and in intracellular structures and form a physical complex. Remarkably, OPN3 can bind retinal, but does not mediate light-induced signaling in melanocytes. Our results identify a novel function for OPN3 in the regulation of the melanogenic pathway in epidermal melanocytes. Our results reveal a light-independent function for the poorly characterized OPN3 and a novel pathway that greatly expands our understanding of melanocyte and skin physiology.SignificanceOur data reveals a novel function for the non-visual opsin OPN3 in regulating the pigmentation of human melanocytes by interacting with and modulating the activity of MC1R.

scholarly journals Was skin cancer a selective force for black pigmentation in early hominin evolution?

2014 ◽  
Vol 281 (1781) ◽  
pp. 20132955 ◽  
Author(s):  
Mel Greaves
Keyword(s):  
Skin Cancer ◽  
Skin Pigmentation ◽  
Selective Force ◽  
Melanocortin 1 Receptor ◽  
Hominin Evolution ◽  
Black Skin ◽  
Impact On Survival ◽  
Genetically Determined ◽  
Risk Of Cancer ◽  
Black Pigmentation

Melanin provides a crucial filter for solar UV radiation and its genetically determined variation influences both skin pigmentation and risk of cancer. Genetic evidence suggests that the acquisition of a highly stable melanocortin 1 receptor allele promoting black pigmentation arose around the time of savannah colonization by hominins at some 1–2 Ma. The adaptive significance of dark skin is generally believed to be protection from UV damage but the pathologies that might have had a deleterious impact on survival and/or reproductive fitness, though much debated, are uncertain. Here, I suggest that data on age-associated cancer incidence and lethality in albinos living at low latitudes in both Africa and Central America support the contention that skin cancer could have provided a potent selective force for the emergence of black skin in early hominins.

Ultrastructure of melanocyte-keratinocyte interactions and pigment transfer in vitro

1978 ◽  
Vol 36 (2) ◽  
pp. 650-651
Author(s):  
Raul I. Garcia ◽  
Evelyn A. Flynn ◽  
George Szabo
Keyword(s):  
Direct Injection ◽  
Skin Pigmentation ◽  
Freeze Fracture ◽  
Pigment Granule ◽  
Time Lapse ◽  
Ultrastructural Level ◽  
Lanthanum Tracer ◽  
A Cell

Skin pigmentation in mammals involves the interaction of epidermal melanocytes and keratinocytes in the structural and functional unit known as the Epidermal Melanin Unit. Melanocytes(M) synthesize melanin within specialized membrane-bound organelles, the melanosome or pigment granule. These are subsequently transferred by way of M dendrites to keratinocytes(K) by a mechanism still to be clearly defined. Three different, though not necessarily mutually exclusive, mechanisms of melanosome transfer have been proposed: cytophagocytosis by K of M dendrite tips containing melanosomes, direct injection of melanosomes into the K cytoplasm through a cell-to-cell pore or communicating channel formed by localized fusion of M and K cell membranes, release of melanosomes into the extracellular space(ECS) by exocytosis followed by K uptake using conventional phagocytosis. Variability in methods of transfer has been noted both in vivo and in vitro and there is evidence in support of each transfer mechanism. We Have previously studied M-K interactions in vitro using time-lapse cinemicrography and in vivo at the ultrastructural level using lanthanum tracer and freeze-fracture.

Dynamics of hepatic and peripheral insulin effects suggest common rate-limiting step in vivo

Diabetes ◽  
1993 ◽  
Vol 42 (2) ◽  
pp. 296-306 ◽  
Author(s):  
D. C. Bradley ◽  
R. A. Poulin ◽  
R. N. Bergman
Keyword(s):  
Rate Limiting Step ◽  
Limiting Step ◽  
Rate Limiting

Conjugates of Classical DNA/RNA Binder with Nucleobase: Chemical, Biochemical and Biomedical Applications

2019 ◽  
Vol 26 (30) ◽  
pp. 5609-5624
Author(s):  
Dijana Saftić ◽  
Željka Ban ◽  
Josipa Matić ◽  
Lidija-Marija Tumirv ◽  
Ivo Piantanida
Keyword(s):  
Molecular Weight ◽  
Small Molecules ◽  
Biomedical Applications ◽  
Protein Targets ◽  
New Class ◽  
Rna Targets ◽  
Covalently Linked ◽  
Structural Aspects

: Among the most intensively studied classes of small molecules (molecular weight < 650) in biomedical research are small molecules that non-covalently bind to DNA/RNA, and another intensively studied class is nucleobase derivatives. Both classes have been intensively elaborated in many books and reviews. However, conjugates consisting of DNA/RNA binder covalently linked to nucleobase are much less studied and have not been reviewed in the last two decades. Therefore, this review summarized reports on the design of classical DNA/RNA binder – nucleobase conjugates, as well as data about their interactions with various DNA or RNA targets, and even in some cases protein targets are involved. According to these data, the most important structural aspects of selective or even specific recognition between small molecule and target are proposed, and where possible related biochemical and biomedical aspects were discussed. The general conclusion is that this, rather new class of molecules showed an amazing set of recognition tools for numerous DNA or RNA targets in the last two decades, as well as few intriguing in vitro and in vivo selectivities. Several lead research lines show promising advancements toward either novel, highly selective markers or bioactive, potentially druggable molecules.

Targeted Delivery of Natural Bioactives and Lipid-nanocargos against Signaling Pathways Involved in Skin Cancer

2020 ◽  
Vol 27 ◽  
Author(s):  
Mohammad Kashif Iqubal ◽  
Aiswarya Chaudhuri ◽  
Ashif Iqubal ◽  
Sadaf Saleem ◽  
Madan Mohan Gupta ◽  
...  
Keyword(s):  
Skin Cancer ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Targeted Delivery ◽  
Skin Pigmentation ◽  
Wnt Signaling Pathway ◽  
Human Beings ◽  
Radiation Chemical ◽  
Cell Leukemia Virus Type ◽  
Human T Cell

: At present, skin cancer is a widespread malignancy in human beings. Among diverse population types, Caucasian populations are much more prone in comparison to darker skin populations due to the comparative lack of skin pigmentation. Skin cancer is divided into malignant and non-melanoma skin cancer, which is additionally categorized as basal and squamous cell carcinoma. The exposure to ultraviolet radiation, chemical carcinogen (polycyclic aromatic hydrocarbons, arsenic, tar, etc.), and viruses (herpes virus, human papillomavirus, and human T-cell leukemia virus type-1) are major contributing factors of skin cancer. There are distinct pathways available through which skin cancer develops, such as the JAKSTAT pathway, Akt pathway, MAPKs signaling pathway, Wnt signaling pathway, to name a few. Currently, several targeted treatments are available, such as monoclonal antibodies, which have dramatically changed the line of treatment of this disease but possess major therapeutic limitations. Thus, recently many phytochemicals have been evaluated either alone or in combination with the existing synthetic drugs to overcome their limitations and have found to play a promising role in the prevention and treatment. In this review, complete tracery of skin cancer, starting from the signaling pathways involved, newer developed drugs with their targets and limitations along with the emerging role of natural products alone or in combination as potent anticancer agents and their molecular mechanism involved has been discussed. Apart from this, various nanocargos have also been mentioned here, which can play a significant role in the management and treatment of different types of skin cancer.

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