New Benzimidazothiazolone Derivatives as Tyrosinase Inhibitors with Potential Anti-Melanogenesis and Reactive Oxygen Species Scavenging Activities.
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ABSTRACT:
SUBMITTER: Jung HJ
PROVIDER: S-EPMC8301170 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The rate-determining role of tyrosinase makes it a critical component in the mechanism that is responsible for melanogenesis. Thirteen (Z)-5-(substituted benzylidene)-3-phenyl-2-thioxothiazolidin-4-one ((Z)-BPTT) analogs were designed based on the structural features of two potent tyrosinase inhibitors, viz. (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-thioxothiazolidin-4-one (5-HMT) and (Z)-2-(2,4-dihydroxybenzylidene)benzo[4,5]imidazo[2,1-b]thiazol-3(2H)-one (compound I). The trisubstituted double bond geometry of the (Z)-BPTT analogs that were generated by Knoevenagel condensation was determined using vicinal 1H and 13C coupling constants in 13C NMR spectra. Four analogs, numbers 1-3 and 6, inhibited mushroom tyrosinase 9 to 29 times more potently than kojic acid did. Kinetic study results indicated that these four analogs inhibited mushroom tyrosinase competitively and this was supported by docking simulation. Also, docking results using human tyrosinase suggested that analogs 2 and 3 might be potent human tyrosinase inhibitors. In vitro studies using B16F10 cells (a melanoma cell line) showed that analogs 1, 2, 3, and 6 inhibited cellular tyrosinase and melanin production more than kojic acid did, without perceptible cytotoxicity. In particular, analog 2, which possesses a catechol group, exerted an extremely potent anti-melanogenic effect. In addition, analog 2 showed strong scavenging activity against DPPH and ABTS radicals. Furthermore, analog 2 not only reduced ROS levels, which induce melanogenesis, but it also suppressed tyrosinase and MITF (microphthalamia-associated transcription factor) protein levels and the expressions of melanogenesis-related genes. These results suggest that analog 2 is an efficient tyrosinase inhibitor that alleviates melanogenesis by dual mechanisms of (i) the inhibition of melanogenesis-related proteins and genes and (ii) the direct inhibition of tyrosinase activity.
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Project description:Reactive oxygen species (ROS) are signaling molecules essential for plant responses to abiotic and biotic stimuli as well as for multiple developmental processes. They are produced as byproducts of aerobic metabolism and are affected by adverse environmental conditions. The ROS content is controlled on the side of their production but also by scavenging machinery. Antioxidant enzymes represent a major ROS-scavenging force and are crucial for stress tolerance in plants. Enzymatic antioxidant defense occurs as a series of redox reactions for ROS elimination. Therefore, the deregulation of the antioxidant machinery may lead to the overaccumulation of ROS in plants, with negative consequences both in terms of plant development and resistance to environmental challenges. The transcriptional activation of antioxidant enzymes accompanies the long-term exposure of plants to unfavorable environmental conditions. Fast ROS production requires the immediate mobilization of the antioxidant defense system, which may occur via retrograde signaling, redox-based modifications, and the phosphorylation of ROS detoxifying enzymes. This review aimed to summarize the current knowledge on signaling processes regulating the enzymatic antioxidant capacity of plants.
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Project description:Pneumonia, such as acute lung injury (ALI), has been a type of lethal disease that is generally caused by uncontrolled inflammatory response and excessive generation of reactive oxygen species (ROS). Herein, we report Fe-curcumin-based nanoparticles (Fe-Cur NPs) with nanozyme functionalities in guiding the intracellular ROS scavenging and meanwhile exhibiting anti-inflammation efficacy for curing ALI. The nanoparticles are noncytotoxic when directing these biological activities. Mechanism studies for the anti-inflammation aspects of Fe-Cur NPs were systematically carried out, in which the infected cells and tissues were alleviated through downregulating levels of several important inflammatory cytokines (such as TNF-α, IL-1β, and IL-6), decreasing the intracellular Ca2+ release, inhibiting NLRP3 inflammasomes, and suppressing NF-κB signaling pathways. In addition, we performed both the intratracheal and intravenous injection of Fe-Cur NPs in mice experiencing ALI and, importantly, found that the accumulation of such nanozymes was enhanced in lung tissue (better than free curcumin drugs), demonstrating its promising therapeutic efficiency in two different administration methods. We showed that the inflammation reduction of Fe-Cur NPs was effective in animal experiments and that ROS scavenging was also effectively achieved in lung tissue. Finally, we revealed that Fe-Cur NPs can decrease the level of macrophage cells (CD11bloF4/80hi) and CD3+CD45+ T cells in mice, which could help suppress the inflammation cytokine storm caused by ALI. Overall, this work has developed the strategy of using Fe-Cur NPs as nanozymes to scavenge intracellular ROS and as an anti-inflammation nanodrugs to synergistically cure ALI, which may serve as a promising therapeutic agent in the clinical treatment of this deadly disease. Fe-Cur NP nanozymes were designed to attenuate ALI by clearing intracellular ROS and alleviating inflammation synergistically. Relevant cytokines, inflammasomes, and signaling pathways were studied.
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Project description:BackgroundThe development of Plasmodium resistance to the last effective anti-malarial drugs necessitates the urgent development of new anti-malarial therapeutic strategies. To this end, plants are an important source of new molecules. The objective of this study was to evaluate the anti-malarial effects of Terminalia albida, a plant used in Guinean traditional medicine, as well as its anti-inflammatory and antioxidant properties, which may be useful in treating cases of severe malaria.MethodsIn vitro antiplasmodial activity was evaluated on a chloroquine-resistant strain of Plasmodium falciparum (K-1). In vivo efficacy of the plant extract was measured in the experimental cerebral malaria model based on Plasmodium berghei (strain ANKA) infection. Mice brains were harvested on Day 7-8 post-infection, and T cells recruitment to the brain, expression levels of pro- and anti-inflammatory markers were measured by flow cytometry, RT-qPCR and ELISA. Non-malarial in vitro models of inflammation and oxidative response were used to confirm Terminalia albida effects. Constituents of Terminalia albida extract were characterized by ultra-high performance liquid chromatography coupled with high resolution mass spectrometry. Top ranked compounds were putatively identified using plant databases and in silico fragmentation patterns.ResultsIn vitro antiplasmodial activity of Terminalia albida was confirmed with an IC50 of 1.5 ?g/mL. In vivo, Terminalia albida treatment greatly increased survival rates in P. berghei-infected mice. Treated mice were all alive until Day 12, and the survival rate was 50% on Day 20. Terminalia albida treatment also significantly decreased parasitaemia by 100% on Day 4 and 89% on Day 7 post-infection. In vivo anti-malarial activity was related to anti-inflammatory properties, as Terminalia albida treatment decreased T lymphocyte recruitment and expression of pro-inflammatory markers in brains of treated mice. These properties were confirmed in vitro in the non-malarial model. In vitro, Terminalia albida also demonstrated a remarkable dose-dependent neutralization activity of reactive oxygen species. Twelve compounds were putatively identified in Terminalia albida stem bark. Among them, several molecules already identified may be responsible for the different biological activities observed, especially tannins and triterpenoids.ConclusionThe traditional use of Terminalia albida in the treatment of malaria was validated through the combination of in vitro and in vivo studies.
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Project description:Rosmarinic acid (RosA), an important polyphenol, is known for its antioxidant and anti-inflammatory activities. However, its application in theranostics has been rarely reported. Therefore, a new single-molecule anti-inflammatory theranostic compound containing RosA would be of great interest. A gadolinium (Gd) complex of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) and RosA (Gd(DO3A-RosA)(H2O)) was synthesized and examined for use as a single-molecule theranostic agent. Its kinetic stability is comparable to that of clinically used macrocyclic magnetic resonance imaging contrast agents. In addition, its relaxivity is higher than that of structurally analogous Gd-BT-DO3A. This agent was evaluated for inflammatory targeting magnetic resonance contrast and showed strong and prolonged enhancement of imaging in inflamed tissues of mice. The theranostic agent also possesses antioxidant and anti-inflammatory activities, as evidenced by reactive oxygen species scavenging, superoxide dismutase activity, and inflammatory factors. The novel RosA-conjugated Gd complex is a promising theranostic agent for the imaging of inflamed tissues, as well as for the treatment of inflammation and oxidative stress.
| S-EPMC7464237 | biostudies-literature
Project description:Abscisic acid stress ripening (ASR1) protein is a small hydrophilic, low molecular weight, and stress-specific plant protein. The gene coding region of ASR1 protein, which is induced under high salinity in rice (Oryza sativa Ilmi), was cloned into a yeast expression vector pVTU260 and transformed into yeast cells. Heterologous expression of ASR1 protein in transgenic yeast cells improved tolerance to abiotic stresses including hydrogen peroxide (H(2)O(2)), high salinity (NaCl), heat shock, menadione, copper sulfate, sulfuric acid, lactic acid, salicylic acid, and also high concentration of ethanol. In particular, the expression of metabolic enzymes (Fba1p, Pgk1p, Eno2p, Tpi1p, and Adh1p), antioxidant enzyme (Ahp1p), molecular chaperone (Ssb1p), and pyrimidine biosynthesis-related enzyme (Ura1p) was up-regulated in the transgenic yeast cells under oxidative stress when compared with wild-type cells. All of these enzymes contribute to an alleviated redox state to H2O2-induced oxidative stress. In the in vitro assay, the purified ASR1 protein was able to scavenge ROS by converting H(2)O(2) to H(2)O. Taken together, these results suggest that the ASR1 protein could function as an effective ROS scavenger and its expression could enhance acquired tolerance of ROS-induced oxidative stress through induction of various cell rescue proteins in yeast cells.
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Project description:We previously reported (E)-β-phenyl-α,β-unsaturated carbonyl scaffold ((E)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosinase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (E)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds 1c (IC50 = 18.09 ± 0.25 μM), 1h (IC50 = 4.14 ± 0.10 μM), and 2a (IC50 = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC50 = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhibition.
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| S-EPMC7948594 | biostudies-literature
Project description:A broad-spectrum reactive oxygen species (ROS)-scavenging hybrid material (CASCADE) was developed by sequential adsorption of heparin (HEP) and poly(L-lysine) (PLL) polyelectrolytes together with superoxide dismutase (SOD) and horseradish peroxidase (HRP) antioxidant enzymes on layered double hydroxide (LDH) nanoclay support. The synthetic conditions were optimized so that CASCADE possessed remarkable structural (no enzyme leakage) and colloidal (excellent resistance against salt-induced aggregation) stability. The obtained composite was active in decomposition of both superoxide radical anions and hydrogen peroxide in biochemical assays revealing that the strong electrostatic interaction with the functionalized support led to high enzyme loadings, nevertheless, it did not interfere with the native enzyme conformation. In vitro tests demonstrated that ROS generated in human cervical adenocarcinoma cells were successfully consumed by the hybrid material. The cellular uptake was not accompanied with any toxicity effects, which makes the developed CASCADE a promising candidate for treatment of oxidative stress-related diseases.
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Project description:Hypoxia, excessive reactive oxygen species (ROS), and impaired angiogenesis are prominent obstacles to wound healing following trauma and surgical procedures, often leading to the development of keloids and hypertrophic scars. To address these challenges, a novel approach has been proposed, involving the development of a cascade enzymatic reaction-based nanocarriers-laden wound dressing. This advanced technology incorporates superoxide dismutase modified oxygen nanobubbles and catalase modified oxygen nanobubbles within an alginate hydrogel matrix. The oxygen nano chamber functions through a cascade reaction between superoxide dismutase and catalase, wherein excessive superoxide in the wound environment is enzymatically decomposed into hydrogen peroxide, and this hydrogen peroxide is subsequently converted into oxygen by catalase. This enzymatic cascade effectively controls wound inflammation and hypoxia, mitigating the risk of keloid formation. Concurrently, the oxygen nanobubbles release oxygen continuously, thus providing a sustained supply of oxygen to the wound site. The oxygen release from this dynamic system stimulates fibroblast proliferation, fosters the formation of new blood vessels, and contributes to the overall wound healing process. In the rat full-thickness wound model, the cascade reaction-based nano oxygen chamber displayed a notable capacity to expedite wound healing without scarring. Furthermore, in the pilot study of porcine full-thickness wound healing, a notable acceleration of tissue repair was observed in the conceived cascade reaction-based gel treated group within the 3 days post-surgery, which represents the proliferation stage of healing process. These achievements hold significant importance in ensuring the complete functional recovery of tissues, thereby highlighting its potential as a promising approach for enhancing wound healing outcomes.
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