Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors

Melanogenesis is a process to synthesize melanin, which is a primary responsible for the pigmentation of human skin, eye and hair. Although numerous enzymatic catalyzed and chemical reactions are involved in melanogenesis process, the enzymes such as tyrosinase and tyrosinase-related protein-1 (TRP-1) and TRP-2 played a major role in melanin synthesis. Specifically, tyrosinase is a key enzyme, which catalyzes a rate-limiting step of the melanin synthesis, and the downregulation of tyrosinase is the most prominent approach for the development of melanogenesis inhibitors. Therefore, numerous inhibitors that target tyrosinase have been developed in recent years. The review focuses on the recent discovery of tyrosinase inhibitors that are directly involved in the inhibition of tyrosinase catalytic activity and functionality from all sources, including laboratory synthetic methods, natural products, virtual screening and structure-based molecular docking studies.     

Dietary Supplementation of Zinc Nanoparticles and Its Influence on Biology,Physiology and Immune Responses of the Freshwater Prawn,Macrobrachium rosenbergii

The present study was conducted to assess the influence of dietary zinc nanoparticles (size 50 nm) on the growth, biochemical constituents, enzymatic antioxidant levels and the nonspecific immune response of the freshwater prawn, Macrobrachium rosenbergii post larvae (PL). The concentrations of dietary supplement zinc nanoparticles (ZnNPs) were 0, 10, 20, 40, 60 and 80 mg kg^?1 with the basal diet, and the level of Zn in ZnNP-supplemented diets were 0.71, 10.61, 20.73, 40.73, 60.61 and 80.60 mg kg^?1, respectively. ZnNP-incorporated diets were fed to M. rosenbergii PL (initial body weight, 0.18?±?0.02 g) in a triplicate experimental setup for a period of 90 days. ZnNP supplemented feed fed PL up to 60 mg kg^?1 showed significantly (P?<?0.05) improved performance in survival, growth and activities of digestive enzymes (protease, amylase and lipase). The concentrations of biochemical constituents (total protein, total amino acid, total carbohydrate and total lipid), total haemocyte count and differential haemocyte count were elevated in 10–60 mg kg^?1 ZnNP supplemented feed fed PL. However, the PL fed with 80 mg ZnNPs kg^?1 showed negative results. Activities of enzymatic antioxidants [superoxide dismutase (SOD) and catalase (CAT)], metabolic enzymes [glutamate–oxaloacetate transaminase (GOT) and glutamate–pyruvate transaminase (GPT)] and the process of lipid peroxidation (LPO) in the hepatopancreas and muscle showed no significant alterations in 10–60 mg kg^?1 ZnNP supplemented feed fed PL. Whereas, 80 mg ZnNPs kg^?1 supplemented feed fed PL showed significant elevations in SOD, CAT, LPO, GOT and GPT. Therefore, 80 mg ZnNPs kg^?1 was found to be toxic to M. rosenbergii PL. Thus, the study suggests that up to 60 mg ZnNPs kg^?1 can be supplemented for regulating survival, growth and immunity of M. rosenbergii.     

Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase

Aminoacyl-tRNA synthetases (aaRSs) drive protein translation in cells and hence these are essential enzymes across life. Inhibition of these enzymes can halt growth of an organism by stalling protein translation. Therefore, small molecule targeting of aaRS active sites is an attractive avenue from the perspective of developing anti-infectives. Febrifugine and its derivatives like halofuginone (HF) are known to inhibit prolyl-tRNA synthetase of malaria parasite Plasmodium falciparum. Here, we present functional and crystallographic data on P. falciparum prolyl-tRNA synthetase (PfPRS). Using immunofluorescence data, we show that PfPRS is exclusively resident in the parasite cytoplasm within asexual blood stage parasites. The inhibitor HF interacts strongly with PfPRS in a non-competitive binding mode in presence or absence of ATP analog. Intriguingly, the two monomers that constitute dimeric PfPRS display significantly different conformations in their active site regions. The structural analyses presented here provide a framework for development of febrifugine derivatives that can seed development of new anti-malarials.     

Studies of translational misreading in vivo show that the ribosome very efficiently discriminates against most potential errors

Protein synthesis must rapidly and repeatedly discriminate between a single correct and many incorrect aminoacyl-tRNAs. We have attempted to measure the frequencies of all possible missense errors by tRNA, tRNA and tRNA. The most frequent errors involve three types of mismatched nucleotide pairs, U•U, U•C, or U•G, all of which can form a noncanonical base pair with geometry similar to that of the canonical U•A or C•G Watson–Crick pairs. Our system is sensitive enough to measure errors at other potential mismatches that occur at frequencies as low as 1 in 500,000 codons. The ribosome appears to discriminate this efficiently against any pair with non-Watson–Crick geometry. This extreme accuracy may be necessary to allow discrimination against the errors involving near Watson–Crick pairing.     

Sea cucumbers of the Arabian Peninsula and Iran – A review of historical and current research trends

Sea cucumbers are benthic marine invertebrates with immense ecological and commercial value. Processed sea cucumbers known as “Beche-de-mer” are a delicacy in southeast Asian countries with an ever-increasing demand depleting wild stocks on a global scale. Aquaculture techniques are well developed for commercially important species (e.g. Holothuria scabra) to aid in conservation and trade. In the Arabian Peninsula and Iran, where the major land mass is surrounded by marginal seas (Arabian Gulf, Gulf of Oman, Arabian Sea, Gulf of Aden, and Red Sea), studies on sea cucumbers are rather limited and its economic value is underestimated. Historical and current research trends indicate impoverished diversity (82 species) due to environmental extremes. Artisanal fisheries exist for the sea cucumbers of Iran, Oman, and Saudi Arabia, with Yemen and United Arab Emirates (UAE) playing a key role in collection and export to Asian countries. Stock assessment and data on export indicates depletion of natural stocks in Saudi Arabia and Oman. Aquaculture trials of high value species (H. scabra) were successful in Saudi Arabia, Oman and Iran with prospects for further expansion. Research on ecotoxicological properties and bioactive substances conducted in Iran demonstrates an immense research potential. Molecular phylogeny, biology, use in bioremediation, and characterisation of bioactive compounds were identified as potential gaps in research. Expanding aquaculture operations could revive exports and recuperate damaged stocks through sea ranching. Furthermore, regional cooperation, networking, training, and capacity building could help fill the gaps in sea cucumber research, which will aid in its effective conservation and management.     

Iron Oxide Nanoparticles Affects Behaviour and Monoamine Levels in Mice

Iron oxide (Fe₂O₃) nanoparticles (NPs) attract the attention of clinicians for its unique magnetic and paramagnetic properties, which are exclusively used in neurodiagnostics and therapeutics among the other biomedical applications. Despite numerous research findings has already proved neurotoxicity of Fe₂O₃-NPs, factors affecting neurobehaviour has not been elucidated. In this study, mice were exposed to Fe₂O₃-NPs (25 and 50 mg/kg body weight) by oral intubation daily for 30 days. It was observed that Fe₂O₃-NPs remarkably impair motor coordination and memory. In the treated brain regions, mitochondrial damage, depleted energy level and decreased ATPase (Mg²⁺, Ca²⁺ and Na⁺/K⁺) activities were observed. Disturbed ion homeostasis and axonal demyelination in the treated brain regions contributes to poor motor coordination. Increased intracellular calcium ([Ca²⁺]_i) and decreased expression of growth associated protein 43 (GAP43) impairs vesicular exocytosis could result in insufficient signal between neurons. In addition, levels of dopamine (DA), norepinephrine (NE) and epinephrine (EP) were found to be altered in the subjected brain regions in correspondence to the expression of monoamine oxidases (MAO). Along with all these factors, over expression of glial fibrillary acidic protein (GFAP) confirms the neuronal damage, suggesting the evidences for behavioural changes.

     

On the oxidation of 3,4-dihydroxyphenethyl alcohol and 3,4-dihydroxyphenyl glycol by cuticular enzyme(s) from Sarcophaga bullata

The catabolic fate of 3,4-dihydroxyphenethyl alcohol (DHPA) and 3,4-dihydroxyphenylethyl glycol (DHPG) in insect cuticle was determined for the first time using cuticular enzyme(s) from Sarcophaga bullata and compared with mushroom tyrosinase-medicated oxidation. Mushroom tyrosinase converted both DHPA and DHPG to their corresponding quinone derivatives, while cuticular enzyme(s) partly converted DHPA to DHPG. Cuticular enzyme(s)-mediated oxidation of DHPA also accompanied the covalent binding of DHPA to the cuticle. Cuticle-DHPA adducts, upon pronase digestion, released peptides that had bound catechols. 3,4-Dihydroxyphenyl-acetaldehyde, the expected product of side chain desaturation of DHPA, was not formed at all. The presence of N-acetylcysteine, a quinone trap, in the reaction mixture containing DHPA and cuticle resulted in the generation of DHPA-quinone-N-acetylcysteine adduct and total inhibition of DHPG formation. The insect enzyme(s) converted DHPG to its quinone at high substrate concentration and to 2-hydroxy-3′,4′-dihydroxyacetophenone at low concentration. They converted exogenously added DHPA-quinone to DHPG, but acted sluggishly on DHPG-quinone. These results are consistent with the enzymatic transformations of phenoloxidase-generated quinones to quinone methides and subsequent nonenzymatic transformation of the latter to the observed products. Thus, quinone methide formation in insect cuticle seems to be caused by the combined action of two enzymes, phenoloxidase and quinone tautomerase, rather than the action of quinone methide-generating phenoloxidase (Sugumaran: Arch Insect Biochem Physiol 8, 73–88, 1988). It is proposed that DHPA and DHPG in combination can be used effectively to examine the participation of (1) quinone, (2) quinone methide, and (3) dehydro derivative intermediates in the metabolism of 4-alkylcatechols for cuticular sclerotization.     

Efficient translation of long-lived messengers in extracts from dry pea primary axes

Extracts prepared from dry pea (Pisum sativum, L; cv oberon) primary axes translate efficiently their endogenous messengers in an in vitro protein synthesizing system. The native long-lived messengers are biologically fully active and direct the synthesis of a whole range of polypeptides with MW ranging up to 130,000. About 0.5% of the total in vitro synthesized polypeptides are recovered in the immunoprecipitate obtained with pea lectin antiserum. Since about one-fourth of the radioactivity in the immunoprecipitate comigrates with authentic pea lectin it is concluded that about 0.1% of the long-lived messengers code for the lectin.Abbreviations mRNA messenger RNA - mRNP messenger ribonucleoprotein - SDS sodium dodecyl sulphate - HEPES N-2-hydroxyethylpiperazine-N-ethanesulphonic acid - S.A specific activity