In therapeutic interventions associated with melanin hyperpigmentation, tyrosinase is regarded as a target enzyme as it catalyzes the rate-limiting steps in mammalian melanogenesis. Since many known agents have been proven to be toxic, there has been increasing impetus to identify alternative tyrosinase inhibitors, especially from natural sources. In this study, we investigated 900 extracts from Greek plants for potential tyrosinase inhibitive properties. Among the five most potent extracts, the methanol extract of Morus alba wood (MAM) demonstrated a significant reduction in intracellular tyrosinase and melanin content in B16F10 melanoma cells. Bioassay-guided isolation led to the acquisition of twelve compounds: oxyresveratrol (1), kuwanon C (2), mulberroside A (3), resorcinol (4), dihydrooxyresveratol (5), trans-dihydromorin (6), 2,4,3′-trihydroxydihydrostilbene (7), kuwanon H (8), 2,4-dihydroxybenzaldehyde (9), morusin (10), moracin M (11) and kuwanon G (12). Among these, 2,4,3′-trihydroxydihydrostilbene (7) is isolated for the first time from Morus alba and constitutes a novel potent tyrosinase inhibitor (IC50 0.8 ± 0.15). We report here for the first time dihydrooxyresveratrol (5) as a potent natural tyrosinase inhibitor (IC50 0.3 ± 0.05). Computational docking analysis indicated the binding modes of six tyrosinase inhibitors with the aminoacids of the active centre of tyrosinase. Finally, we found both MAM extract and compounds 1, 6 and 7 to significantly suppress in vivo melanogenesis during zebrafish embryogenesis.
Introduction !Collagen is the major structural protein in human skin. Consisting of a triple helix scaffold, the tensile strength of its fibers provide structural support for bones, skin, tendons, ligaments, and blood vessels, and are responsible for a dynamic strength of the skin. Mature dermal collagen is formed from precursor molecules called procollagens [1]. Collagenases, which belong to the family of matrix metalloproteinases (MMPs), are transmembrane zinc endopeptidase enzymes. By digesting collagen and elastin fibers, they play important roles in many processes including tissue remodeling during development, tissue homeostasis, and repair after wounding [2]. However, an over activation due to photoaging and chronical aging leads to alterations in the collagen and elastin composition of the extracellular matrix (ECM) and results in wrinkles, laxity, sagging, and a coarse appearance of the human skin [3,4]. The upregulation of certain MMPs has been shown to promote cancer progression and to induce angiogenesis by two modes. First, by activating growth factors such as the transforming growth factor beta (TGF-β) and the vascular endothelial growth factor (VEGF) and second, by degrading the ECM and E-cadherin molecules, which are important to maintain intercellular interactions [5]. Activity of these enzymes can also be pathologically upregulated in response to UV light exposure (photodamage) or the release of reactive oxygen species (ROS). In addition, in vivo studies prove that UV irradiation results in a reduction of procollagen synthesis [3][4][5]. Several authors have reported that upregulated MMPs and diminished procollagen synthesis are mechanisms involved in natural skin aging [6,7]. On the contrary, Chung et al.[8] considered a reduced collagen production and a rise in MMP levels typical for naturally aged skin, while in photoaged skin both parameters tend to be enhanced. The observed effect results in collagen depletion due to the much higher amount of MMP. The discovery of new substances that can prevent connective tissue damage is of great interest for the pharmaceutical and cosmetic industries, and many studies about matrix-metalloproteinase inhibitors from higher plants can be found in the literature [9-11]. Marine organisms are interesting Abstract ! Matrix metalloproteinases play an important role in extracellular matrix remodeling. Excessive activity of these enzymes can be induced by UV light and leads to skin damage, a process known as photoaging. In this study, we investigated the collagenase inhibition potential of mycosporinelike amino acids, compounds that have been isolated from marine organisms and are known photoprotectants against UV-A and UV-B. For this purpose, the commonly used collagenase assay was optimized and for the first time validated in terms of relationships between enzyme-substrate concentrations, temperature, incubation time, and enzyme stability. Three compounds were isolated from the marine red algae Porphyra sp. and Palmaria palmata, and evaluated for their inhibito...
The discovery of new active natural products is hampered by laborious purification processes that often end up to the re-isolation of known compounds. We demonstrate here that, spectral data reflecting concentration fluctuations of components can correlate statistically with measurable dose-dependent properties on the basis of a Heterocovariance approach deconvoluting the active components structure. Variance of extract constituents was achieved through statistically meaningful collections of plants from different families, genus, and species. This fluctuation was also obtained through the fractionation of a single plant extract by separation techniques. The NMR and HRMS spectra of the extracts and fractions were recorded, as well as their ability to inhibit tyrosinase or 5-lipoxygenase enzymes. Biological activity was statistically correlated with spectral data deciphering the active compounds through the Heterocovariance approach prior to any purification. Natural products (NPs) possess significant and well-documented biological properties representing a bioactivity hotspot in the chemical space. [1] However, the great majority of existing chemodiversity remains still unexplored as only a minute fraction of biodiversity has been chemically characterised. [2] The complexity of plant extracts in terms of number, concentration levels and nature of contained metabolites renders this goal rather challenging. Traditional isolation and scale-up proce-dures are inefficient and often become a bottleneck resulting to the constant re-isolation and re-identification of known compounds. Thus, dereplication methods have been emerged aiming to accelerate and rationalize the entire discovery process. [3] Recently, there is a considerable interest by the NP scientific community to adopt metabolomics approaches introducing a more holistic concept in the analysis of complex mixtures. [4][5][6] Metabolomics have found several applications in the area of NPs by means of metabolic profiling and fingerprinting. [7][8][9] They have been successfully employed for chemotaxonomic studies exploring the proximity of different plant species, origins or organs in respect to their metabolite profile. [10] Interestingly, different metabolomics studies have contributed significantly in the quality assessment of botanical preparations enabling the monitoring of the metabolome composition. [11,12] Metabolomics studies are based on the combined application of spectroscopic techniques and multivariate statistical approaches. [13] Among these lines, specific statistical methods for the analysis of the complex spectroscopic data were developed in order to identify components of a complex mixture. The statistical total correlation spectroscopy (STOCSY) [14] can detect multiple NMR peaks from the same molecule based on their intensities multi-colinearity in a set of NMR spectra. Moreover, correlation can be achieved between MS and NMR data in statistical heterospectroscopy (SHY). [15] It has been reported recently a new approach based on MS and activit...
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