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Fish & Shellfish Immunology May 2024Melanin and the process of melanin synthesis or melanogenesis have central roles in the immune system of insects, and production of melanin-synthesizing enzymes from... (Review)
Review
Melanin and the process of melanin synthesis or melanogenesis have central roles in the immune system of insects, and production of melanin-synthesizing enzymes from their haemocytes may be induced following activation through danger signals. Melanin-containing macrophage-like cells have been extensively studied in amphibians and they are also present in reptiles. In fish, melano-macrophages are especially recognized with respect to melano-macrophage centres (MMCs), hypothesized to be analogues of germinal centres in secondary lymphoid organs of mammals and some birds. Melano-macrophages are in addition present in several inflammatory conditions, in particular melanised focal changes, or black spots, in the musculature of farmed Atlantic salmon, Salmo salar. Melanins are complex compounds that may be divided into different forms which all have the ability to absorb and scatter light. Other functions include the quenching of free radicals and a direct effect on the immune system. According to the common view held in the pigment cell community, vertebrate melanin synthesis with melanosome formation may only occur in cells of ectodermal origin. However, abundant information suggests that also myeloid cells of ectothermic vertebrates may be classified as melanocytes. Here, we discuss these opposing views and review relevant literature. Finally, we review the current status on the research concerning melanised focal muscle changes that represent the most severe quality problem in Norwegian salmon production, but also other diseases where melano-macrophages play important roles.
Topics: Animals; Melanins; Fishes; Macrophages; Leukocytes; Melanogenesis; Salmo salar; Fish Diseases; Mammals
PubMed: 38522495
DOI: 10.1016/j.fsi.2024.109523 -
International Journal of Biological... 2024Melanocortin 1 receptor (MC1R), a receptor of α-melanocyte-stimulating hormone (α-MSH), is exclusively present in melanocytes where α-MSH/MC1R stimulate melanin...
Melanocortin 1 receptor (MC1R), a receptor of α-melanocyte-stimulating hormone (α-MSH), is exclusively present in melanocytes where α-MSH/MC1R stimulate melanin pigmentation through microphthalmia-associated transcription factor M (MITF-M). Toll-like receptor 4 (TLR4), a receptor of endotoxin lipopolysaccharide (LPS), is distributed in immune and other cell types including melanocytes where LPS/TLR4 activate transcriptional activity of nuclear factor (NF)-κB to express cytokines in innate immunity. LPS/TLR4 also up-regulate MITF-M-target melanogenic genes in melanocytes. Here, we propose a molecular target of antimelanogenic activity through elucidating inhibitory mechanism on α-MSH-induced melanogenic programs by benzimidazole-2-butanol (BI2B), an inhibitor of LPS/TLR4-activated transcriptional activity of NF-κB. Ultraviolet B (UV-B)-irradiated skins of HRM-2 hairless mice and α-MSH-activated melanocyte cultures were employed to examine melanogenic programs. Topical treatment with BI2B ameliorated UV-B-irradiated skin hyperpigmentation in mice. BI2B suppressed the protein or mRNA levels of melanogenic markers, such as tyrosinase (TYR), MITF-M and proopiomelanocortin (POMC), in UV-B-exposed and pigmented skin tissues. Moreover, BI2B inhibited melanin pigmentation in UV-B-irradiated co-cultures of keratinocyte and melanocyte cells and that in α-MSH-activated melanocyte cultures. Mechanistically, BI2B inhibited the activation of cAMP response element-binding protein (CREB) in α-MSH-induced melanogenic programs and suppressed the expression of MITF-M at the promoter level. As a molecular target, BI2B primarily inhibited mitogen-activated protein kinase (MAPK) kinase 3 (MKK3)-catalyzed kinase activity on p38. Subsequently, BI2B interrupted downstream pathway of p38-mitogen and stress-activated protein kinase-1 (MSK1)-CREB-MITF-M, and suppressed MITF-M-target melanogenic genes, encoding enzymes TYR, TYR-related protein-1 (TRP-1) and dopachrome tautomerase (DCT) in melanin biosynthesis, and encoding proteins PMEL17 and Rab27A in the transfer of pigmented melanosomes to the overlaying keratinocytes in the skin. Targeting the MKK3-p38-MSK1-CREB-MITF-M pathway was suggested as a rationale to inhibit UV-B- or α-MSH-induced facultative melanogenesis and as a strategy to prevent acquired pigmentary disorders in the skin.
Topics: Animals; Mice; Cyclic AMP Response Element-Binding Protein; Melanins; Toll-Like Receptor 4; p38 Mitogen-Activated Protein Kinases; alpha-MSH; Microphthalmia-Associated Transcription Factor; Lipopolysaccharides; Melanocytes; Hyperpigmentation; Monophenol Monooxygenase; Cell Line, Tumor
PubMed: 38481807
DOI: 10.7150/ijbs.93120 -
Cell Communication and Signaling : CCS Feb 2024Coenzyme Q (CoQ), a novel quinone derivative of Antrodia camphorata, has been utilized as a therapeutic agent (including antioxidant, anti-inflammatory, antiangiogenic,...
The in vitro and in vivo depigmentation activity of coenzyme Q, a major quinone derivative from Antrodia camphorata, through autophagy induction in human melanocytes and keratinocytes.
BACKGROUND
Coenzyme Q (CoQ), a novel quinone derivative of Antrodia camphorata, has been utilized as a therapeutic agent (including antioxidant, anti-inflammatory, antiangiogenic, antiatherosclerotic, and anticancer agents); however, its depigmenting efficiency has yet to be studied.
METHODS
We resolved the depigmenting efficiency of CoQ through autophagy induction in melanoma (B16F10) and melanin-feeding keratinocyte (HaCaT) cells and in vivo Zebrafish model. Then, MPLC/HPLC analysis, MTT assay, Western blotting, immunofluorescence staining, LC3 transfection, melanin formation, GFP-LC3 puncta, AVO formation, tyrosinase activity, and TEM were used.
RESULTS
CoQ-induced autophagy in B16F10 cells was shown by enhanced LC3-II accumulation, ATG7 expression, autophagosome GFP-LC3 puncta, and AVOs formation, and ATG4B downregulation, and Beclin-1/Bcl-2 dysregulation. In α-MSH-stimulated B16F10 cells, CoQ induced antimelanogenesis by suppressing CREB-MITF pathway, tyrosinase expression/activity, and melanin formation via autophagy. TEM data disclosed that CoQ increased melanosome-engulfing autophagosomes and autolysosomes in α-MSH-stimulated B16F10 cells. CoQ-inhibited melanogenesis in α-MSH-stimulated B16F10 cells was reversed by pretreatment with the autophagy inhibitor 3-MA or silencing of LC3. Additionally, CoQ-induced autophagy in HaCaT cells was revealed by enhanced LC3-II accumulation, autophagosome GFP-LC3 puncta and AVO formation, ATG4B downregulation, ATG5/ATG7 expression, and Beclin-1/Bcl-2 dysregulation. In melanin-feeding HaCaT cells, CoQ induced melanin degradation by suppressing melanosome gp100 and melanin formation via autophagy. TEM confirmed that CoQ increased melanosome-engulfing autophagosomes and autolysosomes in melanin-feeding HaCaT cells. Treatment with 3-MA reversed CoQ-mediated melanin degradation in melanin-feeding HaCaT cells. In vivo study showed that CoQ suppressed endogenous body pigmentation by antimelanogenesis and melanin degradation through autophagy induction in a zebrafish model.
CONCLUSIONS
Our results showed that CoQ exerted antimelanogenesis and melanin degradation by inducing autophagy. CoQ could be used in skin-whitening formulations as a topical cosmetic application.
Topics: Animals; Humans; Ubiquinone; Melanins; Zebrafish; Monophenol Monooxygenase; alpha-MSH; Beclin-1; Melanocytes; Keratinocytes; Autophagy; Proto-Oncogene Proteins c-bcl-2; Cell Line, Tumor; Benzoquinones; Polyporales
PubMed: 38408981
DOI: 10.1186/s12964-024-01537-6 -
Membranes Feb 2024Lysosomal degradation of tyrosinase, a pivotal enzyme in melanin synthesis, negatively impacts melanogenesis in melanocytes. Nevertheless, the precise molecular...
Lysosomal degradation of tyrosinase, a pivotal enzyme in melanin synthesis, negatively impacts melanogenesis in melanocytes. Nevertheless, the precise molecular mechanisms by which lysosomes target tyrosinase have remained elusive. Here, we identify RING (Really Interesting New Gene) finger protein 152 (RNF152) as a membrane-associated ubiquitin ligase specifically targeting tyrosinase for the first time, utilizing AlphaScreen technology. We observed that modulating RNF152 levels in B16 cells, either via overexpression or siRNA knockdown, resulted in decreased or increased levels of both tyrosinase and melanin, respectively. Notably, RNF152 and tyrosinase co-localized at the trans-Golgi network (TGN). However, upon treatment with lysosomal inhibitors, both proteins appeared in the lysosomes, indicating that tyrosinase undergoes RNF152-mediated lysosomal degradation. Through ubiquitination assays, we found the indispensable roles of both the RING and transmembrane (TM) domains of RNF152 in facilitating tyrosinase ubiquitination. In summary, our findings underscore RNF152 as a tyrosinase-specific ubiquitin ligase essential for regulating melanogenesis in melanocytes.
PubMed: 38392670
DOI: 10.3390/membranes14020043 -
Journal of Pharmaceutical Analysis Jan 2024Epimedin B (EB) is one of the main flavonoid ingredients present in Maxim., a traditional herb widely used in China. Our previous study showed that EB was a stronger...
Epimedin B (EB) is one of the main flavonoid ingredients present in Maxim., a traditional herb widely used in China. Our previous study showed that EB was a stronger inducer of melanogenesis and an activator of tyrosinase (TYR). However, the role of EB in melanogenesis and the mechanism underlying the regulation remain unclear. Herein, as an extension to our previous investigation, we provide comprehensive evidence of EB-induced pigmentation and and elucidate the melanogenesis mechanism by assessing its effects on the TYR family of proteins (TYRs) in terms of expression, activity, and stability. The results showed that EB increased TYRs expression through microphthalmia-associated transcription factor-mediated p-Akt (referred to as protein kinase B (PKB))/glycogen synthase kinase 3β (GSK3β)/β-catenin, p-p70 S6 kinase cascades, and protein 38 (p38)/mitogen-activated protein (MAP) kinase (MAPK) and extracellular regulated protein kinases (ERK)/MAPK pathways, after which EB increased the number of melanosomes and promoted their maturation for melanogenesis in melanoma cells and human primary melanocytes/skin tissues. Furthermore, EB exerted repigmentation by stimulating TYR activity in hydroquinone- and -phenylthiourea-induced TYR inhibitive models, including melanoma cells, zebrafish, and mice. Finally, EB ameliorated monobenzone-induced depigmentation and through the enhancement of TYRs stability by inhibiting TYR misfolding, TYR-related protein 1 formation, and retention in the endoplasmic reticulum and then by downregulating the ubiquitination and proteolysis processes. These data conclude that EB can target TYRs and alter their expression, activity, and stability, thus stimulating their pigmentation function, which might provide a novel rational strategy for hypopigmentation treatment in the pharmaceutical and cosmetic industries.
PubMed: 38352950
DOI: 10.1016/j.jpha.2023.09.006 -
Nature Communications Feb 2024A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in...
A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport. We develop a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression and presents antitumor activity in vitro and in vivo in murine and patient-derived cutaneous, acral and uveal melanoma models. Furthermore, no systemic or off-tumor severe toxicities are observed in an immunocompetent murine model. The efficacy and safety profile of the TYRP1 CAR-T cell therapy supports the ongoing preparation of a phase I clinical trial.
Topics: Humans; Mice; Animals; Melanoma; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Uveal Neoplasms; Cell- and Tissue-Based Therapy; Membrane Glycoproteins; Oxidoreductases
PubMed: 38336975
DOI: 10.1038/s41467-024-45221-2 -
Clinical, Cosmetic and Investigational... 2024For dermatologists, diversities of human races result in an opportunity to encounter patients with various skin types. Cosmetic procedures have gained more popularity... (Review)
Review
For dermatologists, diversities of human races result in an opportunity to encounter patients with various skin types. Cosmetic procedures have gained more popularity and become more accessible over the past decades. Thus, the selection of appropriate treatment protocol for each patient becomes inevitable. This review will focus on basic knowledge and key points in performing safe cosmetic-related procedures in patients with dark-complexioned skin. In terms of structure and function of the skin, people of color have equal epidermal thickness, corneocyte size and melanocyte number. However, they have more stratum corneum compaction, melanosome dispersion and melanocyte activity than fair skin individuals. Data regarding drug penetration and cutaneous irritation showed conflicting results. Superficial chemical peels and microdermabrasion can be done safely in dark-skinned patients. Medium-depth peel should be used with extreme caution. While deep-depth peel should be avoided at all times due to pigmentary and textural complications. Prolonged treatment interval, use of priming agents and sun protection are recommended. Injectable materials including botulinum toxin and soft tissue augmentation by hyaluronic acid filler can be done harmlessly in dark-skinned patients. Lasers and energy-based devices should be done with caution. Higher melanin dispersion and melanocyte activity acts as competitive chromophore. Pigmentary or textural changes can occur after aggressive treatment protocol. High energy setting, pulse stacking, short wavelength lasers and short treatment interval should be avoided in dark-skinned patients.
PubMed: 38321987
DOI: 10.2147/CCID.S450081 -
Biomolecules & Therapeutics Mar 2024Methyl anthranilate (MA) is a botanical fragrance used in food flavoring with unexplored potential in anti-pigment cosmetics. MA dose-dependently reduced melanin content...
Methyl anthranilate (MA) is a botanical fragrance used in food flavoring with unexplored potential in anti-pigment cosmetics. MA dose-dependently reduced melanin content without affecting cell viability, inhibited dendrite elongation and melanosome transfer in the co-culture system of human melanoma cells (MNT-1) and human keratinocyte cell line (HaCaT), and downregulated melanogenic genes, including tyrosinase, tyrosinase-related protein 1 and 2 (TRP-1, TRP-2). Additionally, MA decreased cyclic adenosine monophosphate (cAMP) production and exhibited a significant anti-pigmentary effect in Melanoderm™. These results suggest that MA is a promising anti-pigmentary agent for replacing or complementing existing anti-pigmentary cosmetics.
PubMed: 38296651
DOI: 10.4062/biomolther.2023.103 -
Scientific Reports Jan 2024Tyrosinase (Tyr) is a key enzyme in the process of melanin synthesis that occurs exclusively within specialized organelles called melanosomes in melanocytes. Tyr is...
Tyrosinase (Tyr) is a key enzyme in the process of melanin synthesis that occurs exclusively within specialized organelles called melanosomes in melanocytes. Tyr is synthesized and post-translationally modified independently of the formation of melanosome precursors and then transported to immature melanosomes by a series of membrane trafficking events that includes endoplasmic reticulum (ER)-to-Golgi transport, post-Golgi trafficking, and endosomal transport. Although several important regulators of Tyr transport have been identified, their precise role in each Tyr transport event is not fully understood, because Tyr is present in several melanocyte organelles under steady-state conditions, thereby precluding the possibility of determining where Tyr is being transported at any given moment. In this study, we established a novel synchronized Tyr transport system in Tyr-knockout B16-F1 cells by using Tyr tagged with an artificial oligomerization domain FM4 (named Tyr-EGFP-FM4). Tyr-EGFP-FM4 was initially trapped at the ER under oligomerized conditions, but at 30 min after chemical dissociation into monomers, it was transported to the Golgi and at 9 h reached immature melanosomes. Melanin was then detected at 12 h after the ER exit of Tyr-EGFP-FM4. By using this synchronized Tyr transport system, we were able to demonstrate that Tyr-related protein 1 (Tyrp1), another melanogenic enzyme, is a positive regulator of efficient Tyr targeting to immature melanosomes. Thus, the synchronized Tyr transport system should serve as a useful tool for analyzing the molecular mechanism of each Tyr transport event in melanocytes as well as in the search for new drugs or cosmetics that artificially regulate Tyr transport.
Topics: Melanosomes; Monophenol Monooxygenase; Melanins; Melanogenesis; Melanocytes
PubMed: 38291221
DOI: 10.1038/s41598-024-53072-6 -
Journal of Biosciences 2024Oculocutaneous albinism (OCA) is characterized by reduced melanin biosynthesis affecting the retina, thus impairing visual function. The disease pathology of OCA is...
Oculocutaneous albinism (OCA) is characterized by reduced melanin biosynthesis affecting the retina, thus impairing visual function. The disease pathology of OCA is poorly understood at the cellular level due to unavailability of suitable biological model systems. This study aimed to develop a disease-specific model for OCA type 1A, the most severe form caused by (tyrosinase) gene mutations, using retinal pigment epithelium (RPE) differentiated from patient-derived human-induced pluripotent stem cells (hiPSCs). A comparative study between healthy and OCA1A RPE cells revealed that while healthy RPE cells exhibited timely onest of pigmentation during differentiation, OCA1A RPE cells failed to pigment even after an extended culture period. This observation was validated by ultrastructural studies using electron microscopy, hinting at melanosome-specific defects. Immunocytochemistry demonstrated abnormal expression patterns of melanogenesis-specific protein markers in OCA1A RPE cells, indicating reduced or absence of melanin synthesis. Next, a quantitative assay was performed to confirm the absence of melanin production in OCA1A RPE cells. Tyrosinase assay showed no activity in OCA1A compared with healthy RPE, suggesting non-functionality of , further corroborated by western blot analysis showing complete absence of the protein. Gene expression by RNA sequencing of healthy and OCA1A RPE cells uncovered differential gene expression associated with lens development, visual perception, transmembrane transporter activity, and key signaling pathways. This disease-in-a-dish model of OCA1A provides an excellent platform to understand disease mechanism, identify potential therapeutic targets, and facilitate gene therapy or gene correction.
Topics: Humans; Melanins; Monophenol Monooxygenase; Induced Pluripotent Stem Cells; Retinal Pigment Epithelium; Albinism, Oculocutaneous
PubMed: 38287676
DOI: No ID Found