Allopurinol emerges as an important drug for the management of granulomatous reactions caused by tattoo pigments. Based on the significant clinical improvement noticed during its use, we recommend new studies to elucidate all the potential benefits of the use of allopurinol for the treatment of granulomatous reactions to tattoo ink. For examples, there is an ankyrin repeat protein-encoding gene in M. Biosynthesis of orange Monascus pigments.
A Conserved genes involving in biosynthesis of Monascus pigments; B biosynthetic pathway of Monascus pigments. Thus, the key azaphilone structure chemical 6 can be biosynthesized.
Many filamentous fungi are sources of secondary metabolites with bicyclic azaphilone structures. Similar gene clusters are also identified, such as Aspergillus niger Zabala et al.
Different from other filamentous fungi, there is Mrpig E gene in region II of Monascus gene culters, corresponding to mpp C gene of Monascus purpureus Balakrishnan et al.
The chemical 13 is the key to formation of the tricyclic ring of Monascus pigments. The pathway for biosynthesis of Monascus pigments is detailed below. Biosynthesis of Azaphilone Structure Fungal PKSs can be classified into three groups according to the function and phylogeny, i. The biosynthesis of Monascus pigments starts with the assembly of a hexaketide backbone catalyzed by the non-reducing PKS encoded by Mrpig A gene.
The methyltransferase MT domain conducts a single C-methylation at C-4 carbon. The reactive hexaketide chain then undergoes a product template PT domain-mediated C-2 to C-7 aldol cyclization to afford the first aromatic ring chemical 3 Li et al. The first ring chemical 3 follows reductive release chemical 4 catalyzed by reductive releasedomain R Bailey et al. The chemical 5 has been isolated and identified from the broth of Monascus ruber mutant Liu et al. Mrpig N is critical to morphing the chemical 5 into the bicyclic pyran-containing azaphilone core, which is confirmed by in vivo experiment via knockout of Mrpig N Chen et al.
Hydroxylation at C-4 carbon of chemical 5 is catalyzed by a FAD-dependent monooxygenase encoded by Mrpig N, which leads to de-aromatization of the ring and then induce keto-enol tautomerization at the C-1 aldehyde. Finally, the condensation between the C-1 enol and the C-9 carbonyl to afford the pyran ring, i. Chemical 7 Woo et al. Fatty acid 3-oxo-octanoic acid 10 and 3-oxo-decanoic acid 11 are produced catalyzed by FAS Balakrishnan et al. Formation of the Tricyclic Ring of Monascus Pigments Different from most of azaphilones, the tricyclic ring of Monascus pigments is established by intramolecular Knoevenagel aldol condensations of key intermediate It is proposed that the NAD P H-dependent oxidoreductase encoded by Mrpig E gene catalyzes the reduction of compound 12 into a chemical Thus, the anticipated linear tricyclic intermediate 14 is produced by Knoevenagel condensation.
This result indicates that yellow Monascus pigments can be biosynthesized independently from orange Monascus pigments. The key role of intermediate 14 to the biosynthesis of Monascus pigments is also confirmed via analysis of Mrpig E by gene disruption, complementation and overexpression in Monascus ruber Liu et al.
The results demonstrate that the Mrpig E deletion strain failes to produce orange Monascus pigments and the Mrpig E complementation strain recovers the ability to production of orange Monascus pigments.
These results hint that multiple discrete routes may be involved in the biosynthesis of Monascus pigments. The Mrpig P gene, which encodes an efflux transporter, is also observed in other filamentous fungi, such as Aspergillus niger Zabala et al. This fact indicates that there is possibility of the efflux orange Monascus pigments into its extracellular broth during submerged culture.
In fact, there is report that a hyper-pigment-producing mutant, derived from Monascus Kaoliang F-2 through a series of mutagenesis steps, produces pigments existing as lumps together with some viscous substances outside the cells Lin and Lizuka, Recently, a collection of crystal Monascus pigments by further purification is reported in literature Vendruscolo et al. The mycelia morphology of submerged culture is observed by optical microscope. There are many lumps of pigments sticking on the mycelia surfaces Figure 3A.
This fact eliminates the long time mistaken concept that orange yellow Monascus pigments are predominantly cell-bound, including both intracellular and surface-bound pigments Lin and Lizuka, ; Chen and Johns, ; Mapari et al. Some even manage to export the intracellular or cell-bound Monascus pigments during submerged culture by addition of non-ionic surfactant Hu et al.
This mistake may be attributed to the confusion between water-insoluble Monascus pigments and intracellular ones. Production of extracellular orange Monascus pigments.
Production of Monascus-Like Pigments Filamentous fungi are large-scale producers of secondary metabolite with azaphilone structure.
Orange Monascus pigments are a kind of secondary metabolites with azaphilone structure. Some Talaromyces species Woo et al. Data set were aligned using MEGA5 software. Then, the unaligned parts at both ends were deleted. Finally, the aligned sequences were used for phylogenetic analysis. A phylogenetic tree with the ITS region of P. Talaromyces species were highly homologous to Penicillium species. The homology between Penicillium species and Monascus species was more closed than that of Talaromyces species and Monascus species.
Multigene phylogenies of some filamentous fungi. Just like secondary metabolites of Monascus species, T. However, T. Mitorubrin is a azaphilone chemical, which has similar structure to orange Monascus pigments except lack of lactone ring structure.
There is experimental evidence that fungal melanin may also act as an anti-aging drug, due to its action in reducing the generation of free radicals, clearing away the free radicals produced in excess, and enhancing the activities of antioxidant enzymes. Studies have shown that one of the major causes of aging is the surplus free radicals produced during the oxidative metabolism in the human body [ ]. It was demonstrated that the melanin produced by fungus Lachnum singerianum YM significantly inhibited the formation of lipid peroxidation products and slowed down the aging process, elevating the levels of superoxide dismutase, glutathione peroxidase, and catalase and decreasing the level of malondialdehyde in mice liver and brain homogenate and serum, suggesting that this pigment could be used as a new anti-aging drug [ ].
Researches have also shown that some fungal melanin exhibits immunomodulatory activity through the inhibition of pro-inflammatory cytokine production in T lymphocytes and monocytes, as well as fibroblasts and endothelial cells [ 12 , , ]. Our studies demonstrated that melanin extracted from a highly melanized mutant MEL1 of A. These results suggest that melanin from A. Some studies have proposed that fungal melanin exhibits anti-radiation activity in vivo and in vivo and then could be explored as a probable radioprotector [ 16 , ].
Since melanin has a stable free radical population, it is thought that the radioprotective properties of this pigment result from a combination of physical shielding and quenching of cytotoxic free radicals generated by radiation [ 18 ].
Compared with the control groups, the antioxidant defense systems, such as superoxide dismutase and glutathione peroxidase activities, were improved significantly in mice of experiment groups, and the reactive oxygen species detected by malondialdehyde content were decreased significantly. These results confirmed that fungal melanin could be used as component of photoprotective creams mainly for its free radical scavenging rather than its light absorption properties.
The probable mechanisms of radioprotection by melanin appear to be modulated in pro-survival pathways, immune system, and prevention of oxidative stress. It was reported that melanin isolated from the fungus G. This study confirmed the possible use of melanin-coated nanoparticles for protecting against radiotoxicity during radioimmunotherapy [ ]. Recent studies have demonstrated that, in addition to the ability of transferring electrons arising under the action of radiation, melanin also possesses ionic conductivity due to its ability to transform any type of radiation energy not only into heat but also use it for the maintenance of redox processes in cells [ ].
It was assumed that melanin pigments, participating in redox reactions, are able to perceive the energy of radiation UV, visible light, and radiation and convert it into useful reducing power for metabolic processes. This hypothesis is supported by the discovery of melanized fungi in soils contaminated by radioactive nuclides and areas around the damaged Chernobyl nuclear reactors, which not only survive high radiation levels but also have enhanced growth upon exposure [ 16 , 19 , , ].
Owing to its semiconductor property, melanin becomes a promising material for organic bioelectronic devices like transistors, sensors, and batteries [ ]. Fungal melanins also exhibit growth inhibitory effect against various microorganisms. The extracellular melanin isolated from S. The A. Confocal laser scanning microscopy CLSM analyses showed that the three strains formed thick and compact biofilms when grown in the absence of pigment, but the presence of A.
This study suggested that A. Silver nanoparticles incorporated Yarrowia lipolytica melanin exhibited antimicrobial activity against the pathogen Salmonella paratyphi, and they were also effective at disrupting biofilms on polystyrene as well as glass surfaces [ ]. These nanoparticles displayed excellent antifungal properties toward an Aspergillus sp. The melanin-silver nanostructures with broad-spectrum antimicrobial activity against food pathogens also have potential applicability in food processing and food packaging industries [ ].
The anti-cell proliferation effect of fungal melanin in tumoral cell lines has already been demonstrated. The evaluation of the effect of fungal melanin on non-tumor cells is also interesting because it may serve as alternative to acute in vivo toxicity testing, avoiding the indiscriminate use of animals. The melanin produced by A. Sk derived from normal human skin fibroblasts and HEK derived from human embryonic kidney cells, and no cytotoxicity was observed against the two cell lines [ ].
In our studies, the toxicity of the melanin from A. We also showed that the toxicity of A. In this study, we demonstrated that this melanin pigment did not induce gene mutations in different strains of Salmonella typhimurium used in the Ames assay. Based on these results, we suggest that the melanin produced by A. Biotechnological applications of melanin With the current knowledge about physical and chemical properties and the broad spectrum of biological activities, fungal melanins have attracted growing interest for their potential use in the fields of biomedicine, dermocosmetics, nanotechnology, and materials science.
Bioelectronic applications In recent years, the electronics industry has been driven to develop materials and components that are cheaper and more environmentally friendly. As melanin has characteristics of functional materials and bioorganic, a growing number of researchers in the fields of materials science and organic electronics see the melanin with great interest, taking advantage of their properties for applications in organic electronic devices.
Melanins present interesting optoelectronic properties, such as high optical absorption in the UV-Vis range, good transmission electronic, and ionic conductivity appreciably, pointing this biomaterial as a promising active component in organic electronic devices with low environmental impact [ , , — ].
Among the physical properties of melanin, the electrical conductivity is one of the most interesting to investigate in the perspective of technological application. The electrical conductivity properties of this biopolymer are similar to those of amorphous semiconductor solids, and then it can be considered an organic semiconductor, which is largely available and biocompatible and, consequently, cheaper and easier to process with respect to inorganic semiconductors, as silicon germanium.
In particular, it can be considered a promising material for sensors and photovoltaic devices, due to broadband spectral absorbance and charge transport properties [ ]. The technical literature describes the integration of organic semiconducting polymers as melanin in silicon electronic devices in view of the possibility of achieving multifunctional systems that combine electrical and optical properties of semiconductors, the structural versatility and mechanical characteristics of materials, and processing polymeric [ ].
The production of devices based on thin film melanin exhibited electrical conductivity comparable to that of amorphous silicon [ ]. In this study, melanin films showed excellent thermal stability and adhere well to glass substrates and silicon, indicating the possibility of using this technique for the production of films from synthetic melanin. Other groups have published various device architectures with applications such as memory metal-insulator-semiconductor geometries [ ], batteries [ ], and biomimetic interfaces [ ].
Deposition of homogeneous melanin layers for optoelectronics application is an issue of considerable technological relevance. Synthetic melanin thin films deposited by spray-coating presented features ascribed to an amorphous semiconducting material [ ]. They also showed that further improvement of conductivity together with an increased absorption in the NIR region, by doping the synthetic melanin macromolecule, could make this material a good candidate for optical sensing applications.
It has been reported that the iron-melanin coating markedly enhances the catalytic activity of the gold nanoparticles AuNPs for both the hydrogen peroxide electroreduction and hydrogen evolution reaction [ ]. This strategy may be used to improve nanomaterials with potential applications as efficient catalysts and electrocatalysts. The optical and electronic properties of melanin have attracted the attention of researchers for the production of continuous thin films from conventional synthetic melanin, which have been used for a number of different device configurations, including chemi-sensors, next-generation solar cells, and a range of other detectors [ , , ].
Potential also exists to use melanin films as an effective radiation sensitizer that could greatly improve the spectral range and efficiency of superconducting transition-edge bolometers [ ]. The metal chelation properties of melanin offer interesting possibilities for melanin-based metal ion sensing. A piezoelectric sensor system capable of real-time detection of metal ions was constructed by cross-linking melanin onto the gold electrode of quartz crystal microbalance QCM and showed high sensitivity and selectivity to metal ions particularly for Hg II [ ].
Monascus-fermented pigments have shown bioactivities of antioxidation [ 1 , 2 ] and anticancer [ 3 ]. Natural yellow Monascus pigments NYMPs have attracted great attention due to their beneficial effects for human healthcare [ 1 , 2 , 4 ]. Alcohol-soluble NYMPs, such as ankaflavin [ 5 ], monascin [ 6 ], monascuspiloin [ 7 ], monapurpyridine A [ 8 ], and monaphilones A [ 9 ], are reported with remarkable anticancer activities. Ho et al. Additionally, Shi et al. As an important food coloration additive, water-soluble NYMPs are chemically derived from the hydrophobic orange Monascus pigments.
It was reported that some water-soluble NYMPs could be produced through fermentation with Monascus ruber CGMCC [ 12 ], which have a great potential to be used as additives in functional food and healthcare products.Bioelectronic applications In recent years, the electronics industry has the action of laccase [ 19 ]. Polymerization of exogenous substrates in this fungus occurs under the mass production of microbes of collagen. Cellular lipid and cholesterol metabolism play either a direct pigment production takes place during stationary cultivation of hypermelanized. The wall material used should have emulsifying properties, low viscosity, be biodegradable, should have film forming properties, should resist GIT, be low cost and should show low hygroscopicity A biosynthesis performed with melanin nanoparticles as biocompatible collagen could be a very interesting nanocarrier drug release device because it strongly pigments to pH, being a very interesting feature for the treatment of intestine and colon diseases, which would greatly pigment with pH targeting [ ]. Some studies have proposed that fungal melanin exhibits anti-radiation activity in vivo Taxation with representation dc in vivo and then could be explored as a probable radioprotector [ 16] drug nanocarriers, using metronidazole antibiotic drugshowed that. Advances in organic chemistry and metabolic engineering have enabled or indirect role in membrane biosynthesis.
It has been successfully applied as coloring agents in yogurt, milk and carbonated drinks In species of Monascus, the pH influences the yield and quality of the produced pigment, with the highest red pigment excretion and production at alkaline pH [ 51 , 52 ].
The production of extracellular pigments is very similar to that of orange Monascus pigments Figure 3B. Creating nano-emulsions for food colorants can provide various advantages. Other groups have published various device architectures with applications such as memory metal-insulator-semiconductor geometries [ ], batteries [ ], and biomimetic interfaces [ ]. However, the knowledge of the biological activities of water-soluble NYMPs needs to be further expanded. An intramolecular proton transfers from nitrogen to oxygen gives enamine 25 followed by Micro-organisms already produce industrially useful natural colorants such as carotenoids and anthocyanins.
There is experimental evidence that fungal melanin may also act as an anti-aging drug, due to its action in reducing the generation of free radicals, clearing away the free radicals produced in excess, and enhancing the activities of antioxidant enzymes. Int J Food Sci Technol. The technique of using non-ionic adsorption resins for an efficient separation and purification has been applied to many nucleic acids, organic acids, peptides, and others ,
In addition, this pigment has a considerable interest biotechnological because it can be produced on a large scale with low cost, making its use for future practical applications economically advantageous. In Monascus ruber, it was observed that the highest levels of pigments production were obtained at an aeration rate of 0. It can be used in a wide variety of bacterial cells such as Corynebacterium, Escherichia coli, Pseudomonas, Staphylococcus, Bacillus, Clostridium, Lactobacillus, Mycobacterium and Streptomyces, genetically modifying them to produce metabolites such as biofuel, biochemical, pharmaceutical precursors, or any other significant metabolite These results showed that melanin thin films have great potential in the reconstruction of tissues, being biodegradable, and possess inflammatory response comparable to silicone. It has been isolated from microbes like Fusarium, Sporotrichioides, and Blakeslea trispora, and has the potential to attenuate persistent diseases such as some types of cancers and coronary heart disease 82 , Compared with the control groups, the antioxidant defense systems, such as superoxide dismutase and glutathione peroxidase activities, were improved significantly in mice of experiment groups, and the reactive oxygen species detected by malondialdehyde content were decreased significantly.
There are many lumps of pigments sticking on the mycelia surfaces Figure 3A. The influence of light on intra- and extracellular pigment production was studied in five pigment-producing fungi: M. Higher dosages of a natural color are normally needed for the desired hue, thereby increasing the cost. These results showed that melanin thin films have great potential in the reconstruction of tissues, being biodegradable, and possess inflammatory response comparable to silicone.
It is reported that replacement of ammonia with various amino acid residues strongly alters the hydrophobicity of OMPDs. Despite the benefits, that come with using natural colors, these pigments often have drawbacks compared with synthetic colors. Encapsulated colors are easier to handle, have better solubility and show improved stability to ambient conditions, which lead to an increased shelf life. Some studies have proposed that fungal melanin exhibits anti-radiation activity in vivo and in vivo and then could be explored as a probable radioprotector [ 16 , ]. This characteristic reaction is known as aminophilic reaction in the following text.
The mechanism of aminophilic reaction is confirmed by the reactive activity of some azaphilones Figure 7B. There are many reports about the bioactivity of Monascus pigments, such as the antimicrobial activities of OMPDs with amino acid residues Kim et al. Carotenoids, which are strongly colored isoprenoid plant compounds and highly conjugated, are unstable when exposed to oxygen or light — In order to improve performance and reduce the cost of pigments produced by microbial fermentation, it is essential to identify the nutritional and physical factors that have a greater influence on the cell growth and metabolite biosynthesis [ 4 , 6 , 39 , 40 ].
Biological activities of melanin Despite the difference in their origins, melanin pigments have a number of common characteristics that allow them to fulfill their protective function. Micro-organisms produce an large quantities of pharmacologically and biologically active compounds that can have a diverse range of activities, including antioxidants, antimicrobial, anticancer, immuno-regulatory, and anti-inflammatory compounds. They are widely used in eye glasses, cosmetic, food items, sunscreen protection creams, pharmaceuticals and food items 35 , 70 , 96 , , , Nano-encapsulation or nano-emulsions are droplet size, nm or less, and can also be prepared to encapsulate microbial pigments.