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Nature Communications May 2023Sustained drug delivery strategies have many potential benefits for treating a range of diseases, particularly chronic diseases that require treatment for years. For...
Sustained drug delivery strategies have many potential benefits for treating a range of diseases, particularly chronic diseases that require treatment for years. For many chronic ocular diseases, patient adherence to eye drop dosing regimens and the need for frequent intraocular injections are significant barriers to effective disease management. Here, we utilize peptide engineering to impart melanin binding properties to peptide-drug conjugates to act as a sustained-release depot in the eye. We develop a super learning-based methodology to engineer multifunctional peptides that efficiently enter cells, bind to melanin, and have low cytotoxicity. When the lead multifunctional peptide (HR97) is conjugated to brimonidine, an intraocular pressure lowering drug that is prescribed for three times per day topical dosing, intraocular pressure reduction is observed for up to 18 days after a single intracameral injection in rabbits. Further, the cumulative intraocular pressure lowering effect increases ~17-fold compared to free brimonidine injection. Engineered multifunctional peptide-drug conjugates are a promising approach for providing sustained therapeutic delivery in the eye and beyond.
Topics: Animals; Rabbits; Melanins; Drug Delivery Systems; Brimonidine Tartrate; Peptides; Machine Learning
PubMed: 37130851
DOI: 10.1038/s41467-023-38056-w -
Molecules (Basel, Switzerland) Apr 2021This study was performed to clarify the inhibitory effects of cycloheterophyllin on melanin synthesis. In order to elucidate the inhibitory effects of cycloheterophyllin...
This study was performed to clarify the inhibitory effects of cycloheterophyllin on melanin synthesis. In order to elucidate the inhibitory effects of cycloheterophyllin on the B16F10 cell line, cell viability, messenger ribonucleic acid (mRNA) expressions, tyrosinase activity assay, and melanin production assay were measured. The effects of cycloheterophyllin on tyrosinase-related protein 1 ()//tyrosinase ()/microphthalmia-associated transcription factor () mRNA expressions and melanin content were determined. Quantitative real-time RT-PCR showed that cycloheterophyllin decreased the mRNA expression level of genes and melanin production contents than α-MSH-treated B16F10 cells. The tyrosinase activity assay revealed that cycloheterophyllin decreased the melanin production in the B16F10 cells. These data show that cycloheterophyllin increases the whitening effects in the B16F10 cells; thus, cycloheterophyllin is a potent ingredient for skin whitening. Thus, further research on the mechanism of action of cycloheterophyllin for the development of functional materials should be investigated.
Topics: Animals; Antineoplastic Agents; Antioxidants; Biosynthetic Pathways; Dose-Response Relationship, Drug; Flavonoids; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Melanins; Melanoma, Experimental; Mice
PubMed: 33926006
DOI: 10.3390/molecules26092526 -
Optics Express Aug 2022Pump-probe microscopy of melanin in tumors has been proposed to improve diagnosis of malignant melanoma, based on the hypothesis that aggressive cancers disaggregate...
Pump-probe microscopy of melanin in tumors has been proposed to improve diagnosis of malignant melanoma, based on the hypothesis that aggressive cancers disaggregate melanin structure. However, measured signals of melanin are complex superpositions of multiple nonlinear processes, which makes interpretation challenging. Polarization control during measurement and data fitting are used to decompose signals of melanin into their underlying molecular mechanisms. We then identify the molecular mechanisms that are most susceptible to melanin disaggregation and derive false-coloring schemes to highlight these processes in biological tissue. We demonstrate that false-colored images of a small set of melanoma tumors correlate with clinical concern. More generally, our systematic approach of decomposing pump-probe signals can be applied to a multitude of different samples.
Topics: Humans; Melanins; Melanoma; Microscopy; Skin Neoplasms
PubMed: 36242259
DOI: 10.1364/OE.469506 -
MBio Jun 2022Contamination of food and feed with toxin-producing fungi is a major threat in agriculture and for human health. The filamentous fungus Alternaria alternata is one of...
Contamination of food and feed with toxin-producing fungi is a major threat in agriculture and for human health. The filamentous fungus Alternaria alternata is one of the most widespread postharvest contaminants and a weak plant pathogen. It produces a large variety of secondary metabolites with alternariol and its derivatives as characteristic mycotoxin. Other important phyto- and mycotoxins are perylene quinones (PQs), some of which have anticancer properties. Here, we discovered that the PQ altertoxin (ATX) biosynthesis shares most enzymes with the 1,8-dihydroxynaphthalene (1,8-DHN) melanin pathway. However, melanin was formed in aerial hyphae and spores, and ATXs were synthesized in substrate hyphae. This spatial separation is achieved through the promiscuity of a polyketide synthase, presumably producing a pentaketide (T4HN), a hexaketide (AT4HN), and a heptaketide (YWA1) as products. T4HN directly enters the altertoxin and DHN melanin pathway, whereas AT4HN and YWA1 can be converted only in aerial hyphae, which probably leads to a higher T4HN concentration, favoring 1,8-DHN melanin formation. Whereas the production of ATXs was strictly dependent on the CmrA transcription factor, melanin could still be produced in the absence of CmrA to some extent. This suggests that different cues regulate melanin and toxin formation. Since DHN melanin is produced by many fungi, PQs or related compounds may be produced in many more fungi than so far assumed. Mycotoxins are a major threat for human health. Food safety control relies on the identification of the toxins or the detection of the expression of the respective genes. The latter method, however, relies on the knowledge of the biosynthetic pathway and the key genes. Alternaria alternata is a major food contaminant and produces many different mycotoxins with altertoxins and other perylene quinones as prominent examples. Here, we discovered that the biosynthetic pathway for altertoxins shares most of the enzymes with the dihydroxynaphthalene (DHN) melanin pathway. Because the DHN melanin pathway is widespread among fungi, the production of mycotoxins of the perylene quinone class could be more widespread than so far anticipated.
Topics: Alternaria; Humans; Melanins; Mycotoxins; Perylene; Quinones
PubMed: 35475649
DOI: 10.1128/mbio.00219-22 -
International Journal of Molecular... May 2023Currently, there are three major assaying methods used to validate in vitro whitening activity from natural products: methods using mushroom tyrosinase, human... (Review)
Review
Currently, there are three major assaying methods used to validate in vitro whitening activity from natural products: methods using mushroom tyrosinase, human tyrosinase, and dopachrome tautomerase (or tyrosinase-related protein-2, TRP-2). Whitening agent development consists of two ways, melanin synthesis inhibition in melanocytes and downregulation of melanocyte stimulation. For melanin levels, the melanocyte cell line has been used to examine melanin synthesis with the expression levels of TRP-1 and TRP-2. The proliferation of epidermal surfaced cells and melanocytes is stimulated by cellular signaling receptors, factors, or mediators including endothelin-1, α-melanocyte-stimulating hormone, nitric oxide, histamine, paired box 3, microphthalmia-associated transcription factor, pyrimidine dimer, ceramide, stem cell factors, melanocortin-1 receptor, and cAMP. In addition, the promoter region of melanin synthetic genes including tyrosinase is upregulated by melanocyte-specific transcription factors. Thus, the inhibition of growth and melanin synthesis in gene expression levels represents a whitening research method that serves as an alternative to tyrosinase inhibition. Many researchers have recently presented the bioactivity-guided fractionation, discovery, purification, and identification of whitening agents. Melanogenesis inhibition can be obtained using three different methods: tyrosinase inhibition, copper chelation, and melanin-related protein downregulation. There are currently four different types of inhibitors characterized based on their enzyme inhibition mechanisms: competitive, uncompetitive, competitive/uncompetitive mixed-type, and noncompetitive inhibitors. Reversible inhibitor types act as suicide substrates, where traditional inhibitors are classified as inactivators and reversible inhibitors based on the molecule-recognizing properties of the enzyme. In a minor role, transcription factors can also be downregulated by inhibitors. Currently, the active site copper iron-binding inhibitors such as kojic acid and chalcone exhibit tyrosinase inhibitory activity. Because the tyrosinase catalysis site structure is important for the mechanism determination of tyrosinase inhibitors, understanding the enzyme recognition and inhibitory mechanism of inhibitors is essential for the new development of tyrosinase inhibitors. The present review intends to classify current natural products identified by means of enzyme kinetics and copper chelation to exhibit tyrosinase enzyme inhibition.
Topics: Humans; Melanins; Monophenol Monooxygenase; Copper; Kinetics; Melanocytes; Transcription Factors; Microphthalmia-Associated Transcription Factor; Enzyme Inhibitors
PubMed: 37175965
DOI: 10.3390/ijms24098226 -
Advances in Skin & Wound Care Oct 2023To examine the effectiveness of the ColorMeter DSM III (ColorMeter; Cortex Technology) at grouping individuals by skin tone and measuring erythema/skin discoloration...
OBJECTIVE
To examine the effectiveness of the ColorMeter DSM III (ColorMeter; Cortex Technology) at grouping individuals by skin tone and measuring erythema/skin discoloration after erythema induction across skin tones.
METHODS
This pre/post experimental study induced erythema on a convenience sample of 61 healthy adults. Skin tone at baseline was measured using the ColorMeter, Munsell Soil Color Chart 5YR (Munsell), and Pantone SkinTone Guide (Pantone) and compared with the Eumelanin Human Skin Colour Scale (Eumelanin Scale) groupings. Erythema and melanin values on the arm immediately and after recovery time were compared with baseline values. Melanin was measured at five body regions on the face and arm.
RESULTS
Participants were predominantly women (64% [n = 39] women, 36% [n = 22] men) and young (mean, 28.8 ± 14.3 years); 5% (n = 3) were Hispanic, 26% (n = 16) Asian, 29% (n = 18) Black, 38% (n = 23) White, and 7% (n = 4) identified with more than one race. ColorMeter lightness (L*) and melanin measures were strongly correlated with both Munsell and Pantone values. Munsell skin tone groups were not aligned with Eumelanin Scale groupings. Most participants were in the Eumelanin intermediate-low group, and this changed depending on which body location melanin value was used. The change in erythema from baseline did not differ significantly across skin tone groups at the ulnar head, but on the forearm at the delayed time point, significant differences existed between light and both medium and dark skin tone groups (P = .001; 95% CI, 0.04-0.37).
CONCLUSIONS
The ColorMeter provides an effective objective measure of skin tone and erythema/discoloration across various skin tones and may improve on current standards for detection. The proposed Eumelanin Scale-Modified provides additional sensitivity for persons with medium skin tones.
Topics: Male; Female; Humans; Skin Pigmentation; Melanins; Erythema; Upper Extremity; Technology
PubMed: 37729162
DOI: 10.1097/ASW.0000000000000043 -
Brain Structure & Function Dec 2020The Locus Coeruleus (LC) and the Substantia Nigra (SN) are small brainstem nuclei that change with aging and may be involved in the development of various...
The Locus Coeruleus (LC) and the Substantia Nigra (SN) are small brainstem nuclei that change with aging and may be involved in the development of various neurodegenerative and psychiatric diseases. Magnetization Transfer (MT) MRI has been shown to facilitate LC and the SN visualization, and the observed contrast is assumed to be related to neuromelanin accumulation. Imaging these nuclei may have predictive value for the progression of various diseases, but interpretation of previous studies is hindered by the fact that the precise biological source of the contrast remains unclear, though several hypotheses have been put forward. To inform clinical studies on the possible biological interpretation of the LC- and SN contrast, we examined an agar-based phantom containing samples of natural Sepia melanin and synthetic Cys-Dopa-Melanin and compared this to the in vivo human LC and SN. T and T* maps, MT spectra and relaxation times of the phantom, the LC and the SN were measured, and a two-pool MT model was fitted. Additionally, Bloch simulations and a transient MT experiment were conducted to confirm the findings. Overall, our results indicate that Neuromelanin-MRI contrast in the LC likely results from a lower macromolecular fraction, thus facilitating interpretation of results in clinical populations. We further demonstrate that in older individuals T lengthening occurs in the LC.
Topics: Adult; Female; Humans; Image Enhancement; Locus Coeruleus; Magnetic Resonance Imaging; Male; Melanins; Phantoms, Imaging; Substantia Nigra; Young Adult
PubMed: 33090274
DOI: 10.1007/s00429-020-02153-z -
Cells May 2023Based on traditional pharmacological applications and partial in vitro data, (CA) is proposed to act on skin whitening. However, its functional evaluation and...
Based on traditional pharmacological applications and partial in vitro data, (CA) is proposed to act on skin whitening. However, its functional evaluation and underlying mechanisms have yet to be identified. This study aimed to examine the anti-melanogenesis activity of CA fraction B (CAFB) on UVB-induced skin hyperpigmentation. Forty C57BL/6j mice were exposed to UVB (100 mJ/cm, five times/week) for eight weeks. After irradiation, CAFB was applied to the left ear once a day for 8 weeks (the right ear served as an internal control). The results showed that CAFB significantly reduced melanin production in the ear skin, as indicated by the gray value and Mexameter melanin index. In addition, CAFB treatment notably decreased melanin production in α-MSH-stimulated B16F10 melanocytes, along with a significant reduction in tyrosinase activity. Cellular cAMP (cyclic adenosine monophosphate), MITF (microphthalmia-associated transcription factor), and tyrosinase-related protein 1 (TRP1) were also noticeably downregulated by CAFB. In conclusion, CAFB is a promising ingredient for treating skin disorders caused by the overproduction of melanin and its underlying mechanisms involving the modulation of tyrosinase, mainly mediated by the regulation of the cAMP cascade and MITF pathway.
Topics: Animals; Mice; Melanins; Vincetoxicum; Monophenol Monooxygenase; Microphthalmia-Associated Transcription Factor; Signal Transduction; Mice, Inbred C57BL
PubMed: 37408224
DOI: 10.3390/cells12101390 -
Environmental Microbiology Reports Aug 2022As human activity in space continues to increase, understanding how biological assets respond to spaceflight conditions is becoming more important. Spaceflight...
As human activity in space continues to increase, understanding how biological assets respond to spaceflight conditions is becoming more important. Spaceflight conditions include exposure to ionizing radiation, microgravity, spacecraft vibrations and hypervelocity; all of which can affect the viability of biological organisms. Previous studies have shown that melanin-producing fungi are capable of surviving the vacuum of space and Mars-simulated conditions in Low Earth Orbit. This survival has been associated in part with the protective effects of melanin, but a comparison of fungal viability in the presence or absence of melanin following spaceflight has never been tested. In this study, we evaluated the protective effects of melanin by comparing the viability of melanized and non-melanized clones of Cryptococcus neoformans yeasts following a roundtrip to the International Space Station. Yeast colonies were placed inside two MixStix silicone tubes; one stayed on Earth and the other was transported inside for 29 days before returning to Earth. Post-flight analysis based on colony-forming unit numbers shows that melanized yeast viability was 50% higher than non-melanized yeasts, while no difference was observed between the Earth-bound control samples. The results suggest that fungal melanin could increase the lifespan of biological assets in space.
Topics: Cryptococcus neoformans; Humans; Melanins; Saccharomyces cerevisiae; Space Flight
PubMed: 35852045
DOI: 10.1111/1758-2229.13078 -
Technology and Health Care : Official... 2021Due to the increasing interest in human anti-aging, demand for a higher quality of life, and technological advancement, the development of anti-aging skincare has great...
BACKGROUND
Due to the increasing interest in human anti-aging, demand for a higher quality of life, and technological advancement, the development of anti-aging skincare has great market prospects. Most cosmetic companies develop products driven by the market or focus on the mechanism of action of substances and the behavior of skin; however, little research utilizes skin parameters and large data methodology to develop skincare products.
OBJECTIVE
To instruct consumers to purchase skincare products and to guide skincare research toward the development of customer-targeted products.
METHODS
A total of 815 Chinese subjects (83 male; 732 female) from five different cities were included. We measured 14 indices in each subject, including moisture, transepidermal water loss (TEWL), and sebum levels. We performed multiple regression analysis to understand the relationship between skin indices and aging; a novel approach is shown using the R software.
RESULTS
The exact age at which changes in each skin index occurred could be demonstrated by this method of analysis: 39, 38, 48, 46, and 56 years old with respect to the L value, Melanin, Rt, Rm, and Rz, respectively.
CONCLUSION
With the use of statistical analysis, consumers can be more efficiently targeted and choose suitable products considering particular skin parameter changing points; thus, skincare companies will not only meet customer requirements but also better control budgets.
Topics: Female; Humans; Male; Melanins; Quality of Life; Research Design; Skin; Skin Aging
PubMed: 33682746
DOI: 10.3233/THC-218007